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Pyroptosis in inflammatory diseases and cancer

Pyroptosis in inflammatory diseases and cancer Pyroptosis is a lytic and inflammatory type of programmed cell death that is usually triggered by inflammasomes and executed by gasdermin proteins. The main characteristics of pyroptosis are cell swelling, membrane perforation, and the release of cell contents. In normal physiology, pyroptosis plays a critical role in host defense against pathogen infection. However, excessive pyroptosis may cause immoderate and continuous inflammatory responses that involves in the occurrence of inflammatory diseases. Attractively, as immunogenic cell death, pyroptosis can serve as a new strategy for cancer elimination by inducing pyroptotic cell death and activating intensely antitumor immunity. To make good use of this double-edged sword, the molecular mechanisms, and therapeutic implications of pyroptosis in related diseases need to be fully elucidated. In this review, we first systematically summarize the signaling pathways of pyroptosis and then present the available evidences indicating the role of pyroptosis in inflammatory diseases and cancer. Based on this, we focus on the recent progress in strategies that inhibit pyroptosis for treatment of inflammatory diseases, and those that induce pyroptosis for cancer therapy. Overall, this should shed light on future directions and provide novel ideas for using pyroptosis as a powerful tool to fight inflammatory diseases and cancer. Key words: Pyroptosis, signaling pathway, gasdermin, inflammatory diseases, cancer Introduction The body maintains a dynamic balance between different characteristics from those of apoptosis. cell proliferation and cell death, which plays a Apoptotic cells have intact membranes accompanied significant role in the physiopathological processes of by cell shrinkage, while the membrane integrity of multicellular organisms. Cell death is usually Salmonella-infected macrophages is destroyed by cell categorized as non-programmed cell death and swelling [4, 5]. Hence, a new term, pyroptosis, was programmed cell death (PCD). Pyroptosis is a type of proposed to describe this type of cell death [5], which inflammatory PCD. In 1992, researchers discovered is characterized by cell membrane pore formation, that mouse macrophages infected with Shigella flexneri membrane rupture, cell swelling, and release of cell eventually underwent cell death [1]. Later, researchers contents. The factors released during cell death, such revealed that inflammatory caspase-1 was activated as interleukin-1β (IL-1β) and interleukin-18 (IL-18), during Shigella flexneri- or Salmonella-induced cell amplify the inflammatory effects and activate death [2, 3]. So, this type of cell death was originally immune responses [6, 7]. considered as caspase-dependent apoptosis. Although pyroptosis has been proposed for a However, in 2001, Cookson et al. found that long time, the underlying mechanism was only Salmonella-induced cell death displayed completely uncovered in 2015 upon the discovery and https://www.thno.org Theranostics 2022, Vol. 12, Issue 9 4311 identification of gasdermin D (GSDMD) protein. It Normally, moderate pyroptosis contributes to was found that cleavage of GSDMD by caspase-1 host defense against pathogen infection, but excessive results in the release of its N-terminal domain pyroptosis leads to intemperate inflammatory (GSDMD-NT), which then forms pores in the cell responses, massive cell death, and serious tissue membrane, thus demonstrating that GSDMD is the damage, causing inflammatory or autoimmune central executor of pyroptosis [8]. In addition to diseases. Meanwhile, as a pro-inflammatory type of GSDMD, gasdermin family includes five other cell death, pyroptosis paves a new way for cancer members. The human gasdermin family comprises of elimination by activating antitumor immune GSDMA, GSDMB, GSDMC, GSDMD, GSDME/ response. Here, we first demonstrate different DFNA5, and PVJK/DFNB59. In mice, there are five signaling pathways of pyroptosis to gain deep insight gasdermin members, including GSDMA, GSDMC, into molecular mechanisms. Next, the functions and GSDMD, GSDME, and PJVK/DFNB59, but no therapeutic applications of pyroptosis in GSDMB [9, 10]. All gasdermins except DFNB59 have inflammatory diseases are discussed. Finally, we two conserved domains, an N-terminal effector summarize the roles of pyroptosis in cancer and domain and a C-terminal inhibitory domain [11]. In recent progress in strategies that induce pyroptosis for general, binding of the C-terminal inhibits the cancer therapy (Figure 1), which will point out the pore-forming activity of the N-terminal. In the direction for future research. presence of numerous microbes or other stimulations, gasdermin is cleaved by active caspases or granzymes to liberate the N-terminal domain, which forms large pores in the membrane to release cell contents and execute pyroptosis [12]. The Ragulator-Rag-mTORC1 pathway is required for GSDMD oligomerization and pore formation in macrophages [13]. Cell-surface protein NINJ1 has an essential role in the induction of plasma membrane rupture, which is responsible for releasing intracellular molecules that propagate the inflammatory response [14]. However, the membrane pore can be repaired by endosomal sorting complex required for transport machinery, which initiates by calcium influx through GSDMD pores [15]. The membrane repair can allow cells to restrict pyroptosis and provide insight into cellular survival mechanisms during pyroptosis. The occurrence of pyroptosis often crosstalk with a variety of cell death such as apoptosis and necroptosis. Although these different types of cell Figure 1. Pyroptosis in inflammatory diseases and cancer. death induced by distinct mechanisms, they share some similarities and could be activated alone or simultaneously under different conditions. During Signaling pathways of pyroptosis apoptosis, cleavage of GSDME by caspase-3 mediates progression to pyroptotic cell death [16]. Apoptotic At present, there are mainly four distinct caspase-8, generally correlated to apoptosis, was signaling pathways that have been identified to shown to cleave GSDMD and induce pyroptosis [17]. induce pyroptosis, including canonical and In turn, the inflammatory caspase-1 could activate non-canonical inflammasome pathways, apoptotic apoptosis in the absence of GSDMD. This caspases-mediated pathway, and granzymes-based caspase-1-induced apoptosis depends on caspase-3 pathway (Figure 2). In these signaling pathways, and involves caspase-9 [18]. Crosstalk between gasdermin proteins are the final executioners, which necroptosis and pyroptosis was also discovered need to be cleaved by upstream caspases or recently. Mixed-lineage kinase domain-like protein, granzymes. Caspases can be categorized into the executioner of necroptosis, can also activate inflammatory and apoptotic caspases based on NLRP3 inflammasome to promote the maturation of function [21]. Commonly, caspases-1/4/5/11 belong IL-18 and IL-1β [19]. However, the maturation and to inflammatory caspases, which play key roles in the release of cytokines are independent of GSDMD from innate immune response by inducing pyroptosis to necroptotic cells [20]. interrupt replication of invading pathogens, and by https://www.thno.org Theranostics 2022, Vol. 12, Issue 9 4312 processing pro-inflammatory cytokines to maturation 25] (Figure 2A). NLRP1 is composed of an N-terminal and release [22]. Activation of inflammatory caspase pyrin domain (PYD), a nucleotide-binding oligomeri- provides the first line of defense against infectious zation domain (NOD), a leucine-rich repeats (LRR), pathogens. Caspase-1 is activated in a multiprotein and a C-terminal caspase recruitment domain complex called the inflammasome in the canonical (CARD) [26]. The PYD is required for combining with pyroptosis pathway. The inflammatory caspase- ASC. NOD involves in adenosine triphosphate 4/5/11 do not need such molecular complex for their (ATP)-dependent activation of the signal. LRR is activation, which were shown to bind lipopolysac- responsible for ligand recognition and auto-inhi- charide (LPS) directly. Apoptotic caspases function bition. CARD takes part in pro-caspase-1 recruitment. predominantly to initiate and execute apoptosis. Anthrax lethal toxin, muramyl dipeptide, and Recent studies have shown that they can serve as the components of Toxoplasma gondii can activate NLRP1 proteases to cleave gasdermins for pyroptosis [27]. NLRP3 consists of an N-terminal PYD, a NOD, induction [16]. The details of each signaling pathway and an LRR, without C-terminal CRAD. The NLRP3 is of pyroptosis are discussed below. activated by various factors, including bacteria, viruses, fungi, uric acid, reactive oxygen species Canonical inflammasome pathway (ROS), adenosine triphosphoric (ATP), and The canonical inflammasome pathway was the endogenous damage signals [28]. Extracellular ATP first to be discovered. Inflammasomes are induces IL-1β secretion and caspase-1 activation by multi-protein complexes assembled in response to activating the P2X purinoreceptor 7 (P2X7) and pathogen-associated molecular patterns or inducing K efflux [29]. NLRC4 has an N-terminal non-pathogen-related damage-associated molecular CARD domain, a central NBD domain, and a patterns. Generally, inflammasomes are comprised of C-terminal LRR domain. NLRC4 responds to type III intracellular pattern recognition receptors (PRRs), secretory system proteins and flagellin [30]. AIM2 apoptosis-associated speck-like protein containing a holds a PYD domain and a DNA-binding HIN-200 caspase-recruitment domain (ASC), and inflam- domain that can sense bacteria- or viruses-derived matory caspases [23]. The most common PRRs include double-stranded DNA [31]. Pyrin has a PYD domain, nucleotide-binding oligomerization domain-like two B-boxes, and a C-terminal SPRY/PRY domain. receptors (NLRs, including NLRP1, NLRP3, and Pyrin mainly recognizes the inactivating modifica- NLRC4), absent in melanoma 2 (AIM2), and pyrin [24, Figure 2. Schematic illustration of the different pyroptosis pathways. (A) In the canonical inflammasome pathway, pathogen-associated molecular patterns or damage-associated molecular patterns like viruses, bacteria, toxins, ATP, or ROS stimulates inflammasome, which then activates caspas e-1 to cleave GSDMD for pore formation. (B) LPS from Gram-negative bacteria activates caspase-4/5/11 directly, followed by GSDMD cleavage to execute pyroptosis in the non-canonical inflammasome pathway. (C) Apoptotic caspases-mediated pyroptosis pathway can be engaged through mechanisms such as caspase-3/GSDME, caspase-8/GSDMC, caspase-6/GSDMB, and so on. (D) In the granzymes-mediated pathway, GZMA or GZMB derived from cytotoxic lymphocytes can cleave GSDMB or GSDME respectively for pore formation and pyroptosis. https://www.thno.org Theranostics 2022, Vol. 12, Issue 9 4313 tions of host Rho guanosine triphosphatases mediated cleavage of GSDME [39]. Another apoptotic caspase by various bacterial toxins or effectors [25]. Upon that can trigger pyroptosis is caspase-8, which can stimulation of PRRs, pro-caspase-1 is recruited induce the cleavage of GSDMD to elicit pyroptosis directly by CARD-carrying PRRs or indirectly via ASC during Yersinia infection [17, 40]. When transforming to assemble caspase-1-dependent inflammasomes, growth factor-β-activated kinase 1 is inhibited by the which is followed by caspase-1 activation through Yersinia effector YopJ, lysosome Rag-Ragulator self-cleavage. Active caspase-1 not only cleaves served as a platform for activating a Fas-associated inactive IL-1β and IL-18 precursors, but also cleaves death domain/receptor-interacting serine-threonine GSDMD to release GSDMD-NT for pore-formation, protein kinase 1/caspase-8 complex to trigger eventually leading to inflammatory responses and pyroptosis [41]. Besides, caspase-8 can also cleave pyroptosis [32]. The canonical inflammasome GSDMC, liberating the N-terminus of GSDMC to pathway-mediated pyroptosis mainly occurs in form pores in the cancer cell membrane [42]. In immune cells and serves as a host defense mechanism addition, Chao et al. showed that apoptosis-related against pathogen infection. caspase-3/6/7 cleaves GSDMB, thus removing the C-terminal repressor domain, to cause the release of Non-canonical inflammasome pathway the N-terminal effector domain, which perforates the The non-canonical inflammasome pathway is cell membrane and ultimately evokes cell pyroptosis independent of the classical inflammasome complex. [43]. Most Gram-negative bacteria activate the non-canoni- Granzymes-mediated pathway cal inflammasome pathway. Extracellular LPS can induce the expression of type I interferon, which then Recently, studies have shown that natural killer forms a feedback loop and activates type I interferon cells, cytotoxic T lymphocytes, or chimeric antigen receptor to induce caspase-11 expression [33, 34]. receptor T cells derived granzymes, which are Vacuolar Gram-negative bacteria release their LPS delivered by perforin into target cells, can cleave into the cytosol through vacuolar rupture triggered by specific gasdermin family members to induce cancer interferon-inducible guanylate-binding proteins. The cell pyroptosis (Figure 2D). Granzyme A (GZMA) is released LPS can directly bind to and activate the most abundant serine protease of the granzyme caspase-11, which then cleaves GSDMD to promote family, which has traditionally been recognized as a pyroptosis [35, 36] (Figure 2B). In human, caspase-4/5 mediator of cell death. However, there are many can be activated by intracellular LPS. Caspase-4/5/11 reports have shown that GZMA fails to kill target cells cannot cleave pro-IL-18 and pro-IL-1β directly, but K in vitro unless very high concentrations are used efflux caused by GSDMD -NT pores can activate [44-46]. Accumulating evidence now suggests the role NLRP3 and caspase-1, eventually leading to of GZMA in modulating inflammation, such as maturation and release of IL-18 and IL-1β [37]. In inducing the maturation and release of addition, Yang et al. demonstrated that cleavage of pro-inflammatory cytokines [47-49]. Pyroptosis, one the pannexin-1 channel and ATP release occur in a type of cell death that is accompanied by caspase-11-dependent manner upon LPS stimulation, pro-inflammatory cytokines release, may be which then activate ATP-gated ion channel P2X7, associated with GZMA. Recently, Zhou et al found ultimately resulting in K efflux and subsequent that GZMA derived from cytotoxic T lymphocytes NLRP3/caspase-1 activation in bone marrow-derived cleaves GSDMB to form pores in the membrane, macrophages [38]. Therefore, the activation of NLRP3 resulting in pyroptosis of GSDMB-expressing cancer inflammasome induced by the active caspase-11 is cells [50]. So, whether the GZMA can kill cancer cells required for IL-1β processing in the non-canonical through pyroptosis also depends on the expression of inflammasome pathway. GSDMB, which do not express in some human tissue and is absent in mouse. Natural killer cell-derived Apoptotic caspases-mediated pathway granzyme B (GZMB) can directly cleave GSDME at In addition to inflammatory caspase-1/4/5/11, the same site that is cleaved by caspase-3, leading to some apoptotic caspases can also trigger pyroptosis the release of the effector N-terminal, which (Figure 2C). Chemotherapy drugs can induce perforates the cell membrane [51]. GZMB induces caspase-3-mediated apoptosis, if the target cells GSDME-dependent pyroptosis in tumor targets both express GSDME, the activated caspase-3 can cleave directly by cleaving GSDME and indirectly by GSDME to induce pyroptosis, which switches the activating caspase-3. The direct cleavage of GSDME mode of cell death. Wang et al. found that cisplatin by GZMB provides a simple mechanism and pathway and other conventional chemotherapy drugs can for triggering inflammatory death. Caspase-resistant induce pyroptosis through caspase-3-mediated cancer cells should be susceptible to this direct https://www.thno.org Theranostics 2022, Vol. 12, Issue 9 4314 pathway, provided that the cancer cells express significantly reduce infarct size by inhibiting the GSDME. Granzymes-mediated cancer cell pyroptosis ATPase activity of NLRP3 [60, 61]. The small molecule may amplify the inflammatory response in the tumor 16673-34-0 prevents NLRP3 oligomerization in microenvironment (TME), thereby recruiting more cardiomyocytes and limits myocardial injury after immune cells for antitumor immunity. myocardial ischemia-reperfusion in the mouse model [62]. MCC950 is shown to inhibit NLRP3-induced Inhibiting pyroptosis to treat ASC oligomerization, by which reducing infarct size, inflammatory diseases improving cardiac remodeling, and preventing left ventricular dysfunction in a pig model of MI [63]. In normal physiology, moderate pyroptosis Colchicine acts upstream of NLRP3 to block the plays an important role in the host defense against opening of P2X7 channel and interfere with ASC pathogenic microorganisms [52, 53]. However, polymerization [64, 65]. Treatment with colchicine dysregulated inflammatory response and cell death successfully attenuates NLRP3 inflammasome caused by overactivated pyroptosis may be involved activity, improves cardiac function, and prolongs in the pathological progression of many diseases [54, survival after MI [66]. 55], especially inflammatory diseases. Herein, we mainly discuss the role and therapeutic potential of pyroptosis in inflammatory diseases, like Table 1. Potential strategies targeting pyroptosis to treat cardiovascular diseases cardiovascular diseases, liver diseases, and nervous system diseases. Targets Agents Disease model Findings Ref. NLRP3 INF4E IRI in mouse Reduces infarct size at 60 min [60] Cardiovascular diseases OLT1177 IRI in mouse Limits infarct size and preserves [61] left ventricular contractile function Cardiovascular diseases are the primary cause of 6673-34-0 IRI in mouse Limits the infarct size [62] MCC950 MI in pig Reduces infarct size and preserves [63] patient suffering and high mortality worldwide. cardiac function Recently, many studies have shown that pyroptosis is Colchicine MI in mouse Improves chronic cardiac function [66] and survival closely related to the occurrence and development of Melatonin Atherosclerosis in Reduces the atherosclerotic plaque [67] cardiovascular diseases, such as atherosclerosis, mouse in aorta ischemia-reperfusion injury (IRI), and myocardial PDA@M IRI in rat Decreases the infarct size [68] and improves the cardiac function infarction (MI). Caspase-1 VX-765 IRI in rat Reduces infarction and preserves [69] The pathogenesis of atherosclerosis involves ventricular function smooth muscle cell proliferation and migration, Besides the inhibitors that directly affect NLRP3, endothelial cell dysfunction, pro-inflammatory there are agents that can suppress the activity of cytokine secretion, and cell death [56]. Previous NLRP3 indirectly. Zhang et al. showed that the studies have illustrated that pyroptosis in macro- anti-inflammatory agent melatonin can prevent phages, endothelial cells, and smooth muscle cells are endothelial cell pyroptosis by regulating the signaling related to the progression of atherosclerosis [57]. Duewell et al. showed that cholesterol crystals can pathway of maternally expressed gene 3/miR-223/ NLRP3 in atherosclerosis [67]. Wang et al. showed activate caspase-1 through the NLRP3 inflammasome, that melatonin reduced cigarette smoke extract- which cleaves pro-IL-18 and pro-IL-1β to produce induced pyroptosis by inhibiting the ROS/NLRP3 their mature forms, resulting in inflammation and axis in atherosclerosis [70]. Liraglutide alleviates atherosclerosis formation [58]. NLRP3 inflammasome-mediated pyroptosis in H9c2 IRI involves different types of cell death, among cells, by regulating the sirtuin 1 (SIRT1)/NAPDH which pyroptosis is one of the commonly observed cell death modes. Lou et al. illustrated that microRNA oxidase 4/ROS pathway [71]. Wei et al. reported that a polydopamine-based biomimetic nanoplatform (miR)-424 is markedly upregulated in IRI conditions, (PDA@M) can inhibit pyroptosis to protect the which reduces the expression of cysteine-rich myocardium against IRI. PDA@M consists of a secretory protein LCCL domain-containing 2 and polydopamine core and a macrophage membrane results in the upregulation of caspase-1, IL-18, and IL-1β in cardiac pyroptosis under IRI [59]. shell, to achieve site-specific antioxidative efficacy [68]. The results demonstrated that PDA@M targets Since pyroptosis is involved in the occurrence and progression of cardiovascular diseases, many the infarcted myocardium to suppress the NLRP3/ caspase-1 pathway, thus exerting antioxidative and strategies have been developed to target pyroptosis antipyroptosis functions, suggesting that it may serve for the treatment of these diseases (Table 1, Figure 3). as a potential therapeutic agent for IRI. There are numerous inhibitors of NLRP3 Caspase-1 inhibitors can also inhibit pyroptosis, inflammasome, such as INF4E and OLT1177, when given in mouse model of IRI, the inhibitors and thus, serve to be useful in the treatment of https://www.thno.org Theranostics 2022, Vol. 12, Issue 9 4315 cardiovascular diseases. For example, the caspase-1 NLRP3 inflammasome induces caspase-1 cleavage, inhibitor VX-765 has been shown to produce a and ultimately leads to pyroptosis at the NAFL stage sustained reduction in myocardial infarct size and [76]. The inflammation or fibrosis induced by facilitate preservation of ventricular function in a pyroptosis is more serious at the stage of NASH [74, pre-clinical model of IRI treated with a P2Y receptor 75]. A study proved that GSDMD-NT was antagonist [69]. Moreover, VX-765 was able to reduce upregulated in NAFL and showed higher levels in myocardial infarction in a model of IRI, NASH [77]. GSDMD knockout mice fed with demonstrating that caspase-1 inhibition is an effective methionine-choline deficiency showed milder method for treating pyroptosis-triggered cardiovas- steatosis and inflammation compared with WT mice. cular diseases [72]. These results indicated that pyroptosis executor GSDMD-NT is responsible for the pathogenesis of Liver diseases NAFLD by regulating adipogenesis and secreting Liver diseases are serious problems that inflammatory cytokines [77]. endanger human health worldwide. Recently, studies Due to the serious inflammatory response and have demonstrated that pyroptosis is responsible for liver damage caused by the excessive intake of the progression of liver diseases. When the intestinal alcohol, alcoholic liver disease presents a very high flora is out of balance, the gut microflora can enter the mortality worldwide. However, owing to our poor liver through the intestine-liver axis, which then understanding of the molecular mechanisms triggers pyroptosis in liver cells [73]. underlying the condition, currently, there is still no Non-alcoholic fatty liver disease (NAFLD) has effective treatment strategy for it. It is well established become a serious health problem owing to its high that excessive uptake of alcohol is often related to incidence and high risk of cirrhosis. The roles of cell different forms of cell death, including pyroptosis. necrosis and apoptosis in NAFLD have been Heo et al. discovered that alcohol can decrease the emphasized, but it has only recently been recognized expression of miR-148a through forkhead box O1 that pyroptosis may also play an important role in this (FoxO1) in hepatocytes, which leads to condition. NAFLD is further categorized into overexpression of thioredoxin-interacting protein and non-alcoholic fatty liver (NAFL) and non-alcoholic activation of NLRP3 inflammasome, eventually steatohepatitis (NASH). NAFL is characterized by the inducing pyroptosis in hepatocytes [78]. By reducing accumulation of triglycerides in hepatocytes, while caspase-1-induced pyroptosis, selenium-enriched S. NASH involves massive cell damage, inflammatory platensis displays a protective role in chronic cell infiltration, and hepatocyte expansion [74, 75]. alcohol-induced liver injury [79]. After sensing lipotoxicity-associated ceramide, the Figure 3. Potential strategies targeting pyroptosis for the treatment of cardiovascular diseases. https://www.thno.org Theranostics 2022, Vol. 12, Issue 9 4316 Table 2. Targeting the signaling pathways of pyroptosis to treat liver diseases Targets Agents Disease Mechanism Ref. NLRP3 MCC550 Liver fibrosis Reduces expression of IL-1β and IL-18, and suppresses neutrophil infiltration and [82] hepatic cell death P2X7 inhibitor Liver disease Prevents ATP-mediated activation of NLRP3 [83] Silybin NAFLD Inhibits assembly of NLRP3 inflammasome [84] Dihydroquercetin Alcoholic liver disease Decreases expression of P2X7and NLRP3, and suppresses cleavage of caspase-1 [85] Liraglutide NAFLD Inhibits the NLRP3 inflammasome and pyroptosis activation [86] Downstream of NLRP3 Caspase-1 inhibitor Liver disease Prevents caspase-1-dependent cell death [87] Rosiglitazone NAFLD Inhibits production of hepatic IL-18 [88] IL-1β receptor antagonist Liver fibrosis Block IL-1-mediated inflammation in selective liver fibrotic disease [89] Additionally, liver inflammation has been effect of GSDMD inhibitors requires further shown to be related to pyroptosis during the investigation for the treatment of various liver development of liver fibrosis. The fibrosis-related diseases in the future. proteins are mainly derived from hepatic stellate cells, Nervous system diseases which get activated and produce collagen through Emerging studies imply that pyroptosis may be pyroptosis [80]. In addition to hepatic stellate cells, involved in the pathology of nervous system diseases infiltrated eosinophils have been shown to induce such as ischemic stroke, Parkinson’s disease (PD), and secretion of pro-inflammatory cytokines IL-18 and Alzheimer’s disease (AD). AD is a common IL-1β, or even pyroptotic cell death of hepatocytes, neurodegenerative disease that is characterized by leading to liver fibrosis. The caspase-1 inhibitors dementia and cognitive decline. The main significantly suppress this process, further suggesting pathological features of AD are β-amyloid protein that pyroptosis plays a crucial role in eosinophil- (Aβ) deposition in the extracellular neuritic plaque, induced hepatic fibrosis [81]. neurofibrillary tangles due to aggregation of The above studies indicate that inhibiting abnormally phosphorylated tau protein, vascular pyroptosis might be a potential therapeutic strategy amyloidosis, and neuronal death in the brain. Aβ or for liver diseases. So, there are many researches hyperphosphorylated tau can activate NLRP1, AIM2, targeting pyroptosis for the treatment of liver and NLRP3 inflammasome, eventually resulting in diseases, mainly involving two strategies: direct pyroptosis of neurons both in vitro and in vivo [90, 91]. inhibition of NLRP3 inflammasome and restraining of PD is another neurodegenerative disorder downstream signaling pathways of the NLRP3 characterized by the loss of dopaminergic neurons in inflammasome (Table 2). Qu et al. [82] demonstrated the midbrain. Accumulating evidence demonstrates that MCC950, which is known as an NLRP3 inhibitor, the involvement of pyroptosis in PD. miR-135b significantly alleviates bile duct ligation-induced liver alleviates 1-methyl-4-phenylpyridinium-induced PD fibrosis by reducing IL-18 and IL-1β expression, and in an in vitro model by suppressing FoxO1-induced suppressing neutrophil infiltration and hepatic cell NLRP3 inflammasome activation and pyroptosis, death. P2X7 inhibitors prevent ATP-mediated which suggests that pyroptosis contributes to PD activation of NLRP3 [83]. In addition to these progression [92]. Moreover, the long non-coding RNA inhibitors, some herbal extracts and ingredients can HOTAIR facilitates NLRP3-mediated pyroptosis to inhibit signaling pathways of pyroptosis and reduce aggravate neuronal damage in PD [93]. Taken liver damage. Zhang et al. showed that silybin together, these studies indicate that inhibiting significantly inhibits the assembly of NLRP3 pyroptosis might be a novel therapeutic strategy for inflammasome in mice with NAFLD [84]. A study has PD. demonstrated that dihydroquercetin can decrease the In addition to AD and PD, recent studies have expression of P2X7 and NLRP3, and subsequently demonstrated that pyroptosis of microglia or neurons suppress cleavage of caspase-1 in an animal model of participates in ischemic stroke. Yan et al. showed that alcoholic liver steatosis [85]. Liraglutide, an analog of neuronal pyroptosis is conducive to early ischemic glucagon-like peptide-1, has been shown to inhibit injury through the SIRT1-ROS-tumor necrosis factor NLRP3 inflammasome-mediated pyroptosis and (TNF) receptor-associated factor 6 signaling pathway attenuate mitochondrial dysfunction, which [94]. Moreover, neuron pyroptosis may cause significantly ameliorates NASH [86]. mitochondrial dysfunction, eventually leading to The potential effects of caspase-1 [87], IL-18 [88], increased ROS levels and aggravated ischemic and IL-1β [89] inhibitors have been studied to target injuries. In addition, the diffusion of intracellular the downstream signaling pathways of the NLRP3 inflammatory factors is facilitated by GSDMD- inflammasome. GSDMD is the final executor, but mediated pyroptosis in astrocytes, microglia, and there are very few studies targeting it. The potential https://www.thno.org Theranostics 2022, Vol. 12, Issue 9 4317 infiltrating macrophages, which promotes ischemic all gasdermins can serve as the executors. Pyroptosis brain injury [95-97]. plays a vital role in tumor development and As pyroptosis plays a prominent role in antitumor immunity, by acting as a double-edged pathological process of nervous system diseases, sword that can show both tumor-promoting and many small-molecule inhibitors have been developed tumor-suppressing effects. On the one hand, to target pyroptosis-related signaling pathways for long-term chronic pyroptosis of cancer cells triggered treating these diseases (Figure 4). Inflammasome by the adverse TME is more likely to promote cancer family members have attracted the most attention as progression. Chronic pyroptosis triggers the starting point of pyroptosis. MCC950 is a pro-inflammatory cytokines that facilitate the well-known selective inhibitor of NLRP3, which can formation and maintenance of an inflammatory alleviate the pathological progression of various microenvironment for tumor growth. It has been nervous system diseases, such as AD [98], PD [99], reported that GSDME-mediated pyroptosis promotes and ischemic stroke [94]. Furthermore, salidroside can the development of colitis-associated colorectal cancer suppress NLRP3-dependent pyroptosis to ameliorate by releasing high-mobility group box protein 1, which PD [100]. In addition, as an antagonist of cyclic induces tumor cell proliferation and the expression of GMP-AMP synthase and AIM2 inflammasome, A151 proliferating nuclear antigen through the ERK1/2 prevents pyroptosis of microglia and reduces infarct pathway [104]. Chronic inflammation and pyroptosis volume, ultimately relieving neurodeficits after also involves the development of asbestos-associated ischemic stroke [96]. mesothelioma [105]. On the other hand, acute and Downstream of the inflammasome, active immense activation of pyroptosis results in numerous caspase can cleave gasdermin protein and drive immune cells infiltration, which not only induces pyroptosis. Hence, caspase is another attractive target massive cancer cell death but also activates antitumor for inhibiting pyroptosis. For instance, as a caspase-1 immunity to repress tumor growth [106]. The inhibitor, VX-765 can reduce pyroptosis to alleviate antitumor immunity of pyroptosis involves many injury after AD [101] and stroke [102]. Gasdermin respects, which starts with the release of proteins are the final executors of pyroptosis, and damage-associated molecular patterns and there are drugs that target gasdermins directly. Han et inflammatory cytokines that directly modulates the al. showed that necrosulfonamide, which can inhibit innate immune response, to enhance the recruitment GSDMD oligomerization by binding to the amino acid of adaptive immune cells along with increased of C191, suppresses Aβ-triggered neuronal pyroptosis antigen presentation, resulting in extensive immune in vivo [91]. activation. The released inflammatory cytokines IL-1β can induce dendritic cell (DC) maturation, activate CD8 T cells, and inhibit the differentiation of immunosuppressive T regulatory cells [107]. IL-18 plays critical role in natural killer (NK) cell recruitment and activation, as well as Th-1 polarization [108]. All of these alter the immunosuppressive microenvironment and increase tumor-infiltrating lymphocytes. Thus, inducing acute and massive cancer cell pyroptosis is a potential strategy for tumor treatment. Herein, we summarize the latest progress in pyroptosis-based cancer therapy (Table 3), and the related immune methods are also summarized (Table 4). Figure 4. Therapeutic strategies for treating nervous system diseases by targeting pyroptosis. GSDMD-mediated pyroptosis for cancer therapy GSDMD was the first gasdermin discovered to Inducing cancer cell pyroptosis for cancer be associated with pyroptosis. Shi and Kayagaki et al. therapy showed that GSDMD participates in both canonical and non-canonical pyroptosis [8, 36]. To date, it has The mechanisms of pyroptosis in cancer cells been found that both inflammatory caspase-1/4/5/11 and immune cells are different. In cancer cells, and apoptotic caspase-8 can cleave GSDMD to induce inflammasome is not necessary for pyroptosis pyroptosis. induction and other active proteases except caspases are able to cleave gasdermins [103], in which almost https://www.thno.org Theranostics 2022, Vol. 12, Issue 9 4318 Table 3. Inducing cancer cell pyroptosis for cancer therapy Strategy Cancer types Mechanism Ref. GSDMD-mediated pyroptosis for cancer therapy Simvastatin NSCLC NLRP3/caspase-1/GSDMD [109] a-NETA Ovarian cancer Caspase-4/GSDMD [110] Lip-MOF Cervical cancer Caspase/GSDMD [111] TBD-R Breast cancer, cervix carcinoma, and glioblastoma ROS/caspase-1/GSDMD [112] VTPA Breast cancer Lysosomal rupture and ROS/NLRP3/caspase-1/GSDMD [113] AMPCP Melanoma ATP/NLRP3/caspase-1/GSDMD [114] GSDME-mediated pyroptosis for cancer therapy Paclitaxel, cisplatin Lung cancer Caspase-3/GSDME [115] Lobaplatin Colon cancer ROS and pJNK/ Bax/ Cytochrome c/Caspase-3/9/GSDME [116] As2O3-NPs Hepatocellular carcinoma Caspase-3/GSDME [117] DAC+LipoDDP Breast cancer Caspase-3/GSDME [118] DOX/JQ1-IBRN Breast cancer Caspase-3/GSDME [119] 2+ BNP Breast cancer Ca /Cytochrome c/ Caspase-3/GSDME [120] NCyNP Breast, lung, and cervical cancers. CyNH /Cytochrome c/ Caspase-3/GSDME [121] MCPP Colon cancer ROS/ Caspase-3/GSDME [122] GSDMC/B/A-mediated pyroptosis for cancer therapy α-KG Cervical cancer and melanoma ROS/DR6/Caspase-8/GSDMC [123] GSDMB Colon cancer GZMA/GSDMB [50] Phe-BF3+NP-GA3 Cervical and breast cancer Phe-BF3/GSDMA3 [124] Table 4. Summary of the strategies that induce pyroptosis for cancer therapy related to immune methods Strategy Cancer types Immune response Ref. AMPCP Melanoma Remodels ITME and sensitizes tumors to anti-PD-L1 therapy [114] DAC+LipoDDP Breast cancer Secrets IL-1β and HMGB1, induces the DCs maturation, and increases presence of CTLs [118] DOX/JQ1-IBRN Breast cancer Modulates ITME, JQ1 blocks PD-L1 mediated immune evasion, and reduces Tregs [119] BNP Breast cancer Secrets pro-inflammatory factors to induce DC maturation and T cell activation in TDLNs [120] NCyNH2, NCyNP Breast, lung, and cervical cancers. Promotes CTLs infiltration in TME and DCs maturation in TDLNs, synergizes with αPD-1 to [121] induce antitumor immunity and generates an immune memory effect MCPP Colon cancer Initiates adaptive immunity, boosts the PD-1 blockade efficiency, generates immunological memory, [122] and prevents tumor recurrence. GSDMB Colon cancer Promotes CTL-mediated tumor clearance when combined with αPD-1 [50] + + Phe-BF3+NP-GA3 Cervical and breast cancer Increases CD4 , CD8 , and NK cell populations, decreases Tregs and myeloid-derived suppressor [124] cell populations Simvastatin is a well-established anti-hyperlipi- current therapies fail to eradicate colorectal CSCs demic drug that inhibits 3-hydroxy-3-methylglutaryl- effectively. The phenotype of CSCs and their coenzyme A reductase to reduce cholesterol levels. resistance to chemotherapy drugs are related to C-X-C Recently, Wang et al. demonstrated that simvastatin motif chemokine receptor 4 (CXCR4) overexpression can activate NLRP3-caspase-1 pathway to induce in colorectal cancer. Based on this fact, Serna et al. pyroptosis in non-small cell lung cancer (NSCLC) cell constructed a self-assembling toxin nanoparticle, in lines and mouse models [109]. Inhibition of pyroptosis which the CXCR4 ligand T22 was fused with the reduced the effects of simvastatin on cancer cell therapeutic material diphtheria toxin (DITOX) viability and mobility. These data suggest that the (T22-DITOX-H6) [125]. T22 endows the specificity of anti-hyperlipidemic drug simvastatin may serve as a toxin nanoparticles to target and kill CXCR4 -CSCs. novel therapeutic agent for NSCLC via pyroptosis. Protein synthesis was hindered by DITOX, which Qiao et al. reported that 2-(anaphthoyl) ethyl- eventually led to pyroptotic cell death. T22- trimethylammonium iodide (a-NETA) induces DITOX-H6 also showed greater inhibition of tumor pyroptosis of epithelial ovarian cancer cells via the growth compared to that in the control group in vivo. caspase-4/GSDMD pathway [110]. The cytotoxic Thus, owing to the specific CXCR4 targeting and effect of a-NETA was strongly blocked by knockdown effective cytotoxicity of DITOX, this nanoparticle can of either GSDMD or caspase-4 in ovarian cancer cells. efficiently eliminate apoptotic-resistant CXCR4 Treatment with a-NETA significantly decreased the colorectal CSCs through pyroptosis, demonstrating a size of the epithelial ovarian tumors in vivo. These promising method for colorectal cancer therapy. results imply that a-NETA may be a promising To a certain degree, cellular survival depends on antitumor molecule for epithelial ovarian cancer ion homeostasis. Altering the concentration of a therapy through pyroptosis. specific ion is usually used as a strategy to trigger Owing to their high self-renewal and clonogenic different forms of cell death. Nevertheless, because capacity, cancer stem cells (CSCs) are regarded as the the ion balance is tightly regulated by cells, the root of tumors. However, due to drug resistance, the investigation of certain ions influence on cells in a https://www.thno.org Theranostics 2022, Vol. 12, Issue 9 4319 controlled manner has been obstructed. Specific expression of caspase-1 and GSDMD in 4T1 cells after hybrid metal-organic framework (MOF) nanoparticles different treatments. The results showed that serve as a promising candidate for transporting ions caspase-1 activation and GSDMD cleavage were stealthily into cells and releasing an overdose of ions enhanced upon photodynamic therapy with TBD-R. in a controlled manner. Ploetz et al. designed a Together, this study provides a pyroptosis-based and lipid-coated MIL-100 consisting of ferric ions and photo-activated powerful approach for cancer cell trimesic acid (Lip-MOFs), to transport high amounts removal. of iron ions into cells [111]. The coated lipid not only The lack of tumor-specific pyroptotic agents in prevents cellular recognition of the ions on the MOF vivo impedes the actual applications of pyroptosis- surface, but also facilitates cellular uptake via based cancer therapy. Nadeem et al. reported the endocytosis. After uptake, the Lip-MOFs transfer to development of a virus-spike tumor-activatable lysosomes and then degrade into trimesic acids and pyroptotic agent (VTPA) for cancer-specific therapy 3+ Fe ions by means of pH-dependent and [113]. The VTPA consists of a manganese dioxide cysteine-involved reduction. Lysosomal rupture and spiky structure and an organosilica-coated iron oxide subsequent pyroptosis are triggered by large amounts nanoparticle (IONP) core (Figure 5A). Protrusions 3+ of Fe ions. The reduced expression of full-length facilitate lysosomal rupture, following which the GSDMD and increased release of IL-1β observed in tumor overexpressed glutathione (GSH) triggers the this study demonstrated that pyroptosis was the degradation of VPTA to release Mn ions and IONPs dominant cell death mode. This protective ion for rapid and persistent ROS generation, which delivery and controlled release to cells may pave the synergistically activates the NLRP3/caspase-1/ way for future applications of similar nanostructures GSDMD signaling pathway for pyroptosis (Figure that may be used to eliminate tumor cells in the acidic 5B). Moreover, VTPA showed excellent tumor growth tumor environment by means of pyroptosis and elicit inhibition via pyroptosis in vivo (Figure 5C). This an immune response simultaneously. In addition, iron study provides a tumor-activatable and was also reported to induce a GSDME-dependent nanostructure-dependent pyroptotic agent, pyroptosis [126]. Iron has been shown to trigger highlighting a novel direction for the development of oxidative stress by elevating ROS. On the one hand, next-generation cancer-specific pyroptotic ROS can activate the NLRP3 inflammasome and then nanomedicine in the future. induce GSDMD-dependent canonical pyroptosis; on With limited T-cell responses, it is challenging to the other hand, iron enhanced ROS can cause the overcome innate or adaptive resistance to immune oxidation of the mitochondrial outer membrane checkpoint inhibitor therapy in solid tumors. As an protein Tom20. Oxidized Tom20 recruits Bax to inflammatory form of PCD, pyroptosis is a promising mitochondria, which promotes the release of strategy for enhancing cancer immunotherapy. Xiong cytochrome c to activate caspase-3, eventually et al. designed a GSH-responsive nanomicelles triggering pyroptosis by inducing GSDME cleavage. prodrug, composed of the adenosine inhibitor α, Hence, iron can induce GSDMD- or β-methylene adenosine 5’ diphosphate (AMPCP) and GSDME-mediated pyroptosis depending on the cell the epigenetic modulator γ-oryzanol (Orz) for tumor context. therapy, which they termed as AOZN (Figure 5D) As an inflammatory form of PCD, pyroptosis is a [114]. When AOZN reaches the tumor site, high GSH promising strategy for fighting against cancer. In an in the TME triggers AMPCP and Orz release. The attempt to reduce side effects and achieve DNA methyltransferase inhibitor Orz can upregulate non-invasiveness, Wu et al. designed a series of the expression of GSDMD, AMPCP acts as an membrane-anchoring photosensitizers to induce ecto-5′-nucleotidase inhibitor to reduce adenosine pyroptosis for cancer cell ablation [112]. 1,1,2,2- levels and increase ATP accumulation, subsequently tetraphe-nylethene-benzo[c] [1,2,5] thiadiazole-2- initiating NLRP3 inflammasome assembly and (diphenyl methylene) malononitrile (TBD) and phenyl caspase-1 activation. Active caspase-1 directly cleaves rings (TBD-R) were conjugated with cationic chains to GSDMD and induces pyroptosis in tumor cells obtain aggregation-induced emission photosensi- (Figure 5E). Moreover, Orz and AMPCP tizers. Upon light irradiation, the produced ROS led synergistically combat the immunosuppressive TME to direct damage to the cell membrane and ablation of (ITME). After treatment with AOZN, a more marked cancer cells. Along with the increase of the increase in CD8- and CD4-positive T cells was membrane-anchoring capability of TBD-R, pyroptosis observed in the tumor tissue, while there is a gradually became the dominant cell death mode. To significant decrease in the frequencies of regulatory T uncover the mechanism of TBD-R-initiated pyroptotic cells and CD8 T cell exhaustion in the AOZN group, cell death, the study also evaluated the protein as compared to those in the control group. https://www.thno.org Theranostics 2022, Vol. 12, Issue 9 4320 Additionally, Orz can sensitize tumors to cancers and is mainly activated by apoptotic caspase-3 anti-programmed death-ligand 1 (PD-L1) therapy by and caspase-8. Chemotherapy can activate caspase-3 increasing the expression of PD-L1 (Figure 5F). In to trigger pyroptosis in GSDME-expressing cancer summary, this work proposes a promising strategy to cells [16, 39]. Zhang et al. showed that the enhance cancer immunotherapy and overcome the chemotherapeutic drug paclitaxel can trigger resistance to immune checkpoint blockers. pyroptosis in A549 cells, which is closely related to the levels of activated caspase-3 and GSDME-NT [115]. GSDME-based pyroptosis for cancer therapy Compared to paclitaxel, cisplatin induced more The expression of GSDME varies in different severe pyroptosis in NSCLC cells, indicating that Figure 5. GSDMD-mediated pyroptosis for cancer therapy. (A) Schematic presentation of the designed virus-spike tumor-activatable pyroptotic agent (VTPA). (B) The molecular mechanism of VTPA triggered pyroptosis in tumor cells. (C) Changes in the tumor volume after different treatments. (D) Schematic illustration of designed nanomicelles loaded with AMPCP and Orz (AOZN) for cancer immunotherapy. (E) The mechanism of pyroptosis induced by AOZN. (F) Tumor growth curves after different treatments. Adapted with permission from [113], copyright 2021 John Wiley and Sons, and [114], copyright 2021 John Wiley and Sons. https://www.thno.org Theranostics 2022, Vol. 12, Issue 9 4321 cisplatin may have more advantages than other drugs inhibitor, resulted in the up-regulation of DFNA5 for the treatment of tumors with high GSDME expression. Subsequently, cisplatin-loaded expression. In addition to cisplatin, lobaplatin is one nanoliposome (LipoDDP) was used to activate of the third-generation antitumor platinum that has caspase-3 and induce pyroptosis in DAC-treated stronger antitumor effects but fewer side effects. tumor cells (Figure 6A). Based on its performance in However, the inflammatory characteristics of terms of antitumor activities and metastasis lobaplatin in tumor treatment have not been reported. inhibition, this combined strategy triggered the Yu et al. showed that lobaplatin induced ROS immunological effects of chemotherapy and provided elevation and c-Jun N-terminal kinase phosphoryla- a novel insight into tumor immunotherapy (Figure tion in HT-29 and HCT116 cells, which further recruit 6B-C). Bax to the mitochondria, and thereby, stimulate the Residual microscopic lesions after surgery and release of cytochrome c, followed by caspase-3/9 the ITME contribute to a high rate of post-operative activation and GSDME cleavage, eventually tumor recurrence and metastasis (TRM). Drug-loaded triggering pyroptosis [116]. This study showed that scaffolds have the potential to inhibit TRM, but the GSDME-mediated pyroptosis is a novel mechanism actual therapeutic effects are limited by the ITME and for eradicating cancer cells using lobaplatin, which is untargeted toxicity from non-selective drug release. of great significance for clinical applications. Zhao et al. constructed an implantable bio-responsive In addition to classical chemotherapy drugs, nanoarray (IBRN) to reprogram the ITME and achieve arsenic trioxide (As O ) can accelerate the accurate tumor targeting in a controlled manner, for 2 3 differentiation of viable cancer cells and reduce the effective post-operative tumor therapy and TRM risk of metastasis, which partly achieves better prevention. The chemotherapeutic DOX and treatment responses with lower recurrence rates than epigenetic modulator JQ1 are packaged into traditional drugs. However, it is challenging to realize hyaluronic acid-modified polydopamine effective As O accumulation inside a solid tumor nanoparticles, which are then linked by a 2 3 with few systemic toxicities. To address this issue, Hu ROS-responsive linker to obtain a tumor-targeted et al. designed a triblock copolymer monomethoxy nanoarray loaded with another part of JQ1 (polyethylene glycol)-poly (d, l-lactide-co-glycolide)- (DOX/JQ1-IBRN) (Figure 6D). Upon reaching the poly (l-lysine) (mPEG-b-PLGA-b-PLL) nano-drug tumor site, high H O triggers the release of JQ1 and 2 2 system to deliver As O (As O -NPs). After the DOX, which realize ITME modulation and induce 2 3 2 3 As O -NPs are internalized by tumor cells, the As O GSDME-dependent pyroptosis, further eliciting 2 3 2 3 is released into the cytoplasm and GSDME is cleaved antitumor immunity and wiping out the residual following caspase-3 activation. The cleaved GSDME tumor completely [119]. The results showed that N-domains form membrane pores, eventually leading DOX/JQ1-IBRN inhibited post-surgical TRM and to pyroptosis. In vivo antitumor study showed that prolonged survival in tumor models with low As O moderately inhibited tumor growth, while toxicity. In summary, IBRN realizes accurate tumor 2 3 As O -NPs substantially reduced tumor growth. pyroptosis and ITME conversion to activate antitumor 2 3 As O -NPs treatment resulted in an increase in the immunity, for effective and safe prevention of TRM, 2 3 protein levels of cleaved caspase-3 and GSDME-NT, thus providing novel insights for post-operative with a decrease in those of Dnmt1, Dnmt3a, and treatment. Dnmt3b, thus uncovering the mechanism of the Pyroptosis is considered an excellent choice to antitumor activity of As O -NPs [117]. These data promote the immune response for cancer therapy, 2 3 provide a new vision and strategy for future because of its pro-inflammatory characteristics. Zhao hepatocellular carcinoma therapy based on pyroptosis et al. designed a biomimetic nanoparticle (BNP) by mediated by As O . fusing a breast cancer membrane shell onto a PLGA 2 3 As mentioned above, the expression of GSDME polymeric core loaded with indocyanine green and in cancer cells varies. It is silenced in some types of DAC, for photo-activated cancer cell pyroptosis and tumors due to the hypermethylation of the cancer immunotherapy. Due to the homing capability GSDME/DFN59 gene; owing to this, of the cancer cell membrane, BNP can effectively GSDME-mediated pyroptosis is absent in these accumulate in the tumor site with low tumors. Fan et al. developed a strategy of combining immunogenicity. The loaded indocyanine green can chemotherapy with DNA demethylation to trigger perforate the tumor cell membrane and induce a 2+ cancer cell pyroptosis, which amplifies the immune sudden increase in cytoplasmic Ca through effect to further eliminate tumors via immune therapy near-infrared (NIR) irradiation, which activates [118]. Pretreatment of tumor cells with decitabine caspase-3 by promoting the release of cytochrome c. (DAC), a commonly used DNA methyltransferase Meanwhile, DAC inhibits DNA methylation, which is https://www.thno.org Theranostics 2022, Vol. 12, Issue 9 4322 followed by upregulation of GSDME, eventually nodes, compared to those upon carrying out other causing pyroptosis. In vivo, the primary and distant treatments, indicating that photo-activated pyroptosis tumor growth was significantly repressed within 28 further induces inspiring antitumor immunity for days of using this strategy. After BNP treatment plus cancer therapy [120]. Together, BNP provides a novel photo-activation, a high percentage of CD8 T cells strategy for photo-activated cancer cell pyroptosis and CD4 T cells were detected in distant tumors and and robust solid tumor immunotherapy with high spleens, and a high rate of mature DCs were detected compatibility. in the primary tumor and tumor-draining lymph Figure 6. GSDME-mediated pyroptosis for cancer therapy. (A) Schematic illustration of the demethylation and immune activation process mediated by decitabine and LipoDDP + + + + + + via pyroptosis. (B) Quantification of CD4 and CD8 T cell-gating on CD3 cells in the tumors. (C) Statistical analysis of CD80 CD86 cell-gating on CD11c cells within tumor-draining lymph nodes. (D) Illustration of the DOX/JQ1-IBRN for post-surgical tumor treatment, involving pyroptosis of tumor cells, conversion of the ITME, and cascade activation of immunity. Adapted with permission from [118], copyright 2019 ACS, and [119], copyright 2020 John Wiley and Sons. https://www.thno.org Theranostics 2022, Vol. 12, Issue 9 4323 Figure 7. GSDMC/B-based pyroptosis for cancer therapy. (A) The working model of α-KG-induced pyroptosis via GSDMC. Adapted with permission from [123], copyright 2021 Springer Nature. (B) Cytotoxic lymphocyte-derived GZMA cleaves GSDMB in cancer cells to perforate the cell membrane and induce pyroptosis. Pyroptosis can effectively eradicate cancer cells GSDMC/B/A-related pyroptosis for cancer by boosting anticancer immunity; however, due to its therapy non-selectivity, most of the current pyroptosis In addition to GSDME and GSDMD, the inducers may cause severe side effects in cancer N-terminal domain of GSDMC/B/A also has the therapy. Wang et al. first reported that the NIR capacity to form pores in the cell membrane, to fluorophore-based hemicyanine CyNH can kill execute pyroptosis. Hou et al. showed that nuclear cancer cells and boost antitumor immunity by PD-L1 (nPD-L1) switches TNF-α-induced apoptosis to inducing pyrolysis. To realize the tumor-specificity of GSDMC-mediated pyroptosis in cancer cells [42]. CyNH , cancer cells high expressing NAD(P)H: Under hypoxic stress, p-Stat3 interacts with PD-L1 quinone oxidoreductase isozyme 1 (NQO1)-respon- and promotes its nuclear translocation, which sive CyNH (NCyNH ) were designed to trigger 2 2 transcriptionally activates GSDMC expression. After pyroptosis and further activate systemic antitumor TNF-α treatment, active caspase-8 cleaves GSDMC to immunity. In addition, NCyNH was further release its N-terminal domain, which forms pores on encapsulated in PEG-b-PLGA as a theranostic the cell membrane, eventually inducing pyroptosis. In nanocarrier (NCyNP) for systemic administration and addition, nPD-L1-switched pyroptosis is required for fluorescence imaging in vivo. NCyNPs combined with tumor necrosis in vivo. In brief, this study found a anti-programmed death-1 (PD-1) enhance the novel function of PD-L1 and identified that antitumor effect and prevent tumor recurrence by caspase-8/GSDMC mediates the pyroptosis pathway producing powerful memory efficacy [120]. Hence, in cancer cells, which facilitates tumor necrosis. the NIR fluorophore-based CyNH may represent a Metabolic homeostasis and metabolites affect novel theranostic agent for initiating tumor cell fate. α-ketoglutarate (α-KG) is an essential pyroptosis selectively and triggering immunotherapy metabolite in the tricarboxylic acid cycle that plays efficiently. To achieve higher tumor specificity, Xiao important roles in many physiological processes, such et al. designed a TME reactive ROS/GSH as oxidative stress reduction and cell death. dual-responsive nano-prodrug loaded with Nevertheless, the role of α -KG in pyroptosis remains photosensitizer purpurin 18 and paclitaxel (MCPP) to unknown. Zhang et al. demonstrated that dimethyl induce GSDME-mediated pyroptosis in cancer cells α-KG can pass through the cell membrane and induce specifically. Upon laser irradiation, ROS produced by the oxidation and endocytosis of death receptor 6 photosensitizer purpurin 18 realizes controlled (DR6) by elevating ROS levels [123]. After DR6 release and triggers cancer cell pyroptosis with internalization, both pro-caspase-8 and GSDMC are paclitaxel via chemo-photodynamic therapy. Pyrop- recruited to the DR6 receptosome, where active totic cancer cells further initiate adaptive immunity caspase-8 cleaves the GSDMC, finally resulting in and boost immune checkpoint blockade efficiency to pyroptosis (Figure 7A). α-KG-induced pyroptosis has prevent tumor growth and recurrence [122]. This been shown to be sufficient for inhibiting tumor study not only provides a highly efficient strategy to growth and metastasis in vivo. Fascinatingly, in an induce pyroptosis in tumor cells specifically, but also acidic environment, α-KG can be reduced to resolves a challenge in immune checkpoint blockade L-2-hydroxyglutarate (L-2HG) by the metabolic via pyroptosis. https://www.thno.org Theranostics 2022, Vol. 12, Issue 9 4324 enzyme malate dehydrogenase 1, which further the role of inflammatory caspases (caspases- boosts ROS and promotes pyroptosis. Treatment with 1/4/5/11) in pyroptosis. Afterwards, researchers lactic acid produces more L-2HG because of the have found that apoptotic caspases (caspases-3/6/8) improved acidic environment, which turns are also involved in the process of pyroptosis. pyroptosis-resistant cancer cells into pyroptosis- Moreover, recent studies have shown that sensitive cancer cells. Collectively, this study links GZMA/GZMB can trigger pyroptosis as well as metabolites with the pyroptosis pathway and caspases. These studies renovate our understanding illustrates how α-KG triggers DR6 endocytosis to of pyroptosis. Future research will continue to update bring about caspase-8/GSDMC-mediated pyroptosis, the novel and precise activation modes of pyroptosis, and thus, has application in cancer therapy. for instance, which caspases or other factors mediate During the period when apoptosis was consi- the cleavage of the GSDMA. dered the dominant form of PCD, granzymes were Generally, GSDMD cleavage by caspase-1 via the thought to kill target cells by means of apoptosis. canonical inflammasome pathway plays an important However, the discovery of pyroptosis has updated role in host defense against pathogen infections. our understanding of PCD. It is important to explore However, excessive inflammatory responses and cell whether gasdermin proteins respond to granzymes death caused by pyroptosis may be involved in and induce pyroptosis. Zhou et al. demonstrated that various diseases, such as cardiovascular diseases, cytotoxic T lymphocyte- or NK cell-derived GZMA nervous system diseases, and liver diseases. Hence, can cleave GSDMB to release its pore-forming many studies have focused on inhibiting pyroptosis to N-terminal domain for pyroptosis induction [50]. treat these diseases by targeting NLRP3, caspase-1, or Moreover, interferon-γ increased the expression of GSDMD. VX-765 is a safe and effective inhibitor of GSDMB to further promote pyroptosis (Figure 7B). caspase-1 that has been proved to be well tolerated in Heterologous overexpression of GZMA-cleavable phase II clinical trial in patients with partial epilepsy. human GSDMB in mouse cancer cells accelerates the Therefore, VX-765 is a clinical-grade drug that could elimination of tumors in vivo. This study identified a potentially be used in other pyroptosis-related novel killing mechanism of cytotoxic lymphocytes diseases. Another anti-pyroptotic drug currently in through gasdermin-mediated pyroptosis, which clinical application is lncRNA NBR2, which regulates ensures sufficient antitumor immunity. endothelial pyroptosis by targeting GSDMD in sepsis. Bioorthogonal chemistry presents a wonderful Nevertheless, due to non-specificity, many current strategy for investigating many biological processes, inhibitors may result in unexpected side effects. such as immunity and cell death in live animals. Further research is needed to improve the specificity Wang et al. constructed a nano-bioorthogonal of pyroptotic inhibitors. In addition, current chemical system, in which gasdermin A3 (GA3) was therapeutic targets for the treatment of these diseases linked to nanoparticles via the trimethylsilyl ether mainly focus on canonical inflammasome signaling, linker (NP-GA3), and this linker could be cleaved by a that is, the caspase-1/GSDMD pathway. It should be cancer-imaging probe phenylalanine trifluoroborate further investigated whether the non-canonical (Phe-BF3) [124]. When HeLa and EMT6 cells were inflammasome pathway or apoptotic caspases- treated with NP-GA3 and Phe-BF3, the cells showed mediated pathway of pyroptosis is implicated in these obvious pyroptotic morphology. It should be noted inflammatory diseases and can serve as therapeutic that only a small fraction of the tumor cells targets. undergoing pyroptosis could erase the entire tumor, Although pyroptosis produces pathogenic which implies the role of the immune system. effects on inflammatory diseases, as a pro-inflam- Furthermore, only one round of injection of NP-GA3 matory cell death, it also paves a new way for cancer and Phe-BF3 could not prevent tumor growth. In clearance by deliberate induction of pyroptotic cell contrast, tumor growth was markedly inhibited by death and intense antitumor immunity. In cancer, one round of injection plus anti-PD-1 therapy, which pyroptosis has been shown to be triggered by almost demonstrates that inflammation induced by all signaling pathways in which GSDME, GSDMD, pyroptosis can trigger robust antitumor immunity GSDMC, or GSDMB serve as the executors. Induction and synergize with immune checkpoint blockade for of pyroptosis to eliminate tumor cells has become a tumor immunotherapy. promising strategy for the treatment of tumor by boosting antitumor immunity. However, gasdermins Conclusion are also expressed in normal tissues. Extensive pyroptosis may cause severe damage to the normal Pyroptosis is a form of inflammatory PCD tissues. Hence, there are several points to be noted for mediated by gasdermin proteins, which are often pyroptosis-based cancer therapy. Firstly, how to activated by caspases. Initially, researchers focused on https://www.thno.org Theranostics 2022, Vol. 12, Issue 9 4325 specifically induce pyroptosis in cancer cells but not recurrence and metastasis; VTPA: virus-spike tumor- in normal cells for cancer therapy. Some studies have activatable pyroptotic agent; α-KG: α-ketoglutarate; designed TME responsive nanodrug to induce α-NETA: 2-(anaphthoyl) ethyl-trimethylammonium pyroptosis in cancer cells specifically. Secondly, how iodide. to visualize pyroptosis in vivo, to further improve its Acknowledgements accuracy. Future studies are urgently needed to develop more precise and tumor-specific pyroptotic This work was supported by the National Key treatments, and more clinical trials are needed to Research and Development Program of China (Nos. explore the potential application of pyroptosis-based 2017YFC1309100 and 2017YFA0205200), National cancer therapy. Natural Science Foundation of China (Nos. 21804104, 91959124, 81671753, 32101147 and 32071406), Abbreviations Innovation Capability Support Program of Shaanxi ASC: apoptosis-associated speck-like protein (Program No. 2022TD-52), Natural Science containing a caspase recruitment domain; AD: Foundation of Shaanxi Province of China alzheimer’s disease; AIM2: absent in melanoma 2; (No. 2020PT-020), The Youth Innovation Team of AMPCP: α, β-methylene adenosine 5’ diphosphate; Shaanxi Universities, Natural Science Basic Research AOZN: AMPCP and Orz loaded nanomicelles; ATP: Plan in Shaanxi Province of China (Nos. 2021JM-147 adenosine triphosphoric acid; Aβ: β-amyloid protein; and 2021JQ-212), and the Fundamental Research BNP: biomimetic nanoparticle; CARD: caspase Funds for the Central Universities (Nos. JB211201, recruitment domain-containing; CSCs: cancer stem JB211202, JB211204). cells; CXCR4: C-X-C motif chemokine receptor 4; Competing Interests DAC: decitabine; DC: dendritic cell; DITOX: diphtheria toxin; DR6: death receptor 6; FoxO1: The authors have declared that no competing forkhead box O1; GA3: gasdermin A3; GSDMD: interest exists. gasdermin D; GSDMD-NT: gasdermin D N-terminal References domain; GSH: glutathione; GZMA: granzyme A; GZMB: granzyme B; IBRN: implantable 1. Zychlinsky A, Prevost MC, Sansonetti PJ. Shigella flexneri induces apoptosis in infected macrophages. Nature. 1992; 358: 167-9. bio-responsive nanoarray; IL-18: interleukin-18; IL-1β: 2. Hilbi H, Chen Y, Thirumalai K, Zychlinsky A. 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Nanostructured toxins for the selective destruction of drug-resistant human CXCR4(+) colorectal cancer stem cells. J Control Release. 2020; 320: 96-104. 126. Zhou B, Zhang JY, Liu XS, Chen HZ, Ai YL, Cheng K, et al. Tom20 senses iron-activated ROS signaling to promote melanoma cell pyroptosis. Cell Res. 2018; 28: 1171-85. Author Biographies Dr. Pengbo Ning received his PhD from Northwest A&F University in 2013. He worked at the College of Veterinary Medicine, Northwest A&F University from 2007 to 2015, and the field of study was genome-wide analysis in interactions between viruses and macrophages. He then moved to the School of Life and Technology, Xidian University, as an Associate Professor, and his research focuses on gene-modified Dr. Zhiping Rao received macrophages and their potential application for her Ph.D. from the Institute of Neuroscience, State cancer immunotherapy and drug delivery. Key Laboratory of Neuroscience, CAS center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences in 2018. She then joined the School of Life and Technology, Xidian University as a lecturer and her research focuses on the programmed cell death and disease treatment, especially ferroptosis and pyroptosis-based cancer therapy. https://www.thno.org Theranostics 2022, Vol. 12, Issue 9 4329 Prof. Zhongliang Wang received his PhD from Institute of chemistry, Chinese Academy of Sciences in 2009. He then moved to the University of Florida as a postdoc fellow working with Professor Y. Charles Cao. In 2013, he joined the Laboratory of Molecular Imaging and Nanomedicine (LOMIN) at the National Institutes of Health (NIH) as a postdoctoral fellow under the supervision of Prof. Xiaoyuan (Shawn) Chen. In 2014, he joined the School of Life and Technology, Xidian University as a Professor and his research focuses on the development of smart and biomimetic materials for diagnostics and therapeutics of various diseases. https://www.thno.org http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Theranostics Pubmed Central

Pyroptosis in inflammatory diseases and cancer

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Pubmed Central
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1838-7640
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10.7150/thno.71086
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Abstract

Pyroptosis is a lytic and inflammatory type of programmed cell death that is usually triggered by inflammasomes and executed by gasdermin proteins. The main characteristics of pyroptosis are cell swelling, membrane perforation, and the release of cell contents. In normal physiology, pyroptosis plays a critical role in host defense against pathogen infection. However, excessive pyroptosis may cause immoderate and continuous inflammatory responses that involves in the occurrence of inflammatory diseases. Attractively, as immunogenic cell death, pyroptosis can serve as a new strategy for cancer elimination by inducing pyroptotic cell death and activating intensely antitumor immunity. To make good use of this double-edged sword, the molecular mechanisms, and therapeutic implications of pyroptosis in related diseases need to be fully elucidated. In this review, we first systematically summarize the signaling pathways of pyroptosis and then present the available evidences indicating the role of pyroptosis in inflammatory diseases and cancer. Based on this, we focus on the recent progress in strategies that inhibit pyroptosis for treatment of inflammatory diseases, and those that induce pyroptosis for cancer therapy. Overall, this should shed light on future directions and provide novel ideas for using pyroptosis as a powerful tool to fight inflammatory diseases and cancer. Key words: Pyroptosis, signaling pathway, gasdermin, inflammatory diseases, cancer Introduction The body maintains a dynamic balance between different characteristics from those of apoptosis. cell proliferation and cell death, which plays a Apoptotic cells have intact membranes accompanied significant role in the physiopathological processes of by cell shrinkage, while the membrane integrity of multicellular organisms. Cell death is usually Salmonella-infected macrophages is destroyed by cell categorized as non-programmed cell death and swelling [4, 5]. Hence, a new term, pyroptosis, was programmed cell death (PCD). Pyroptosis is a type of proposed to describe this type of cell death [5], which inflammatory PCD. In 1992, researchers discovered is characterized by cell membrane pore formation, that mouse macrophages infected with Shigella flexneri membrane rupture, cell swelling, and release of cell eventually underwent cell death [1]. Later, researchers contents. The factors released during cell death, such revealed that inflammatory caspase-1 was activated as interleukin-1β (IL-1β) and interleukin-18 (IL-18), during Shigella flexneri- or Salmonella-induced cell amplify the inflammatory effects and activate death [2, 3]. So, this type of cell death was originally immune responses [6, 7]. considered as caspase-dependent apoptosis. Although pyroptosis has been proposed for a However, in 2001, Cookson et al. found that long time, the underlying mechanism was only Salmonella-induced cell death displayed completely uncovered in 2015 upon the discovery and https://www.thno.org Theranostics 2022, Vol. 12, Issue 9 4311 identification of gasdermin D (GSDMD) protein. It Normally, moderate pyroptosis contributes to was found that cleavage of GSDMD by caspase-1 host defense against pathogen infection, but excessive results in the release of its N-terminal domain pyroptosis leads to intemperate inflammatory (GSDMD-NT), which then forms pores in the cell responses, massive cell death, and serious tissue membrane, thus demonstrating that GSDMD is the damage, causing inflammatory or autoimmune central executor of pyroptosis [8]. In addition to diseases. Meanwhile, as a pro-inflammatory type of GSDMD, gasdermin family includes five other cell death, pyroptosis paves a new way for cancer members. The human gasdermin family comprises of elimination by activating antitumor immune GSDMA, GSDMB, GSDMC, GSDMD, GSDME/ response. Here, we first demonstrate different DFNA5, and PVJK/DFNB59. In mice, there are five signaling pathways of pyroptosis to gain deep insight gasdermin members, including GSDMA, GSDMC, into molecular mechanisms. Next, the functions and GSDMD, GSDME, and PJVK/DFNB59, but no therapeutic applications of pyroptosis in GSDMB [9, 10]. All gasdermins except DFNB59 have inflammatory diseases are discussed. Finally, we two conserved domains, an N-terminal effector summarize the roles of pyroptosis in cancer and domain and a C-terminal inhibitory domain [11]. In recent progress in strategies that induce pyroptosis for general, binding of the C-terminal inhibits the cancer therapy (Figure 1), which will point out the pore-forming activity of the N-terminal. In the direction for future research. presence of numerous microbes or other stimulations, gasdermin is cleaved by active caspases or granzymes to liberate the N-terminal domain, which forms large pores in the membrane to release cell contents and execute pyroptosis [12]. The Ragulator-Rag-mTORC1 pathway is required for GSDMD oligomerization and pore formation in macrophages [13]. Cell-surface protein NINJ1 has an essential role in the induction of plasma membrane rupture, which is responsible for releasing intracellular molecules that propagate the inflammatory response [14]. However, the membrane pore can be repaired by endosomal sorting complex required for transport machinery, which initiates by calcium influx through GSDMD pores [15]. The membrane repair can allow cells to restrict pyroptosis and provide insight into cellular survival mechanisms during pyroptosis. The occurrence of pyroptosis often crosstalk with a variety of cell death such as apoptosis and necroptosis. Although these different types of cell Figure 1. Pyroptosis in inflammatory diseases and cancer. death induced by distinct mechanisms, they share some similarities and could be activated alone or simultaneously under different conditions. During Signaling pathways of pyroptosis apoptosis, cleavage of GSDME by caspase-3 mediates progression to pyroptotic cell death [16]. Apoptotic At present, there are mainly four distinct caspase-8, generally correlated to apoptosis, was signaling pathways that have been identified to shown to cleave GSDMD and induce pyroptosis [17]. induce pyroptosis, including canonical and In turn, the inflammatory caspase-1 could activate non-canonical inflammasome pathways, apoptotic apoptosis in the absence of GSDMD. This caspases-mediated pathway, and granzymes-based caspase-1-induced apoptosis depends on caspase-3 pathway (Figure 2). In these signaling pathways, and involves caspase-9 [18]. Crosstalk between gasdermin proteins are the final executioners, which necroptosis and pyroptosis was also discovered need to be cleaved by upstream caspases or recently. Mixed-lineage kinase domain-like protein, granzymes. Caspases can be categorized into the executioner of necroptosis, can also activate inflammatory and apoptotic caspases based on NLRP3 inflammasome to promote the maturation of function [21]. Commonly, caspases-1/4/5/11 belong IL-18 and IL-1β [19]. However, the maturation and to inflammatory caspases, which play key roles in the release of cytokines are independent of GSDMD from innate immune response by inducing pyroptosis to necroptotic cells [20]. interrupt replication of invading pathogens, and by https://www.thno.org Theranostics 2022, Vol. 12, Issue 9 4312 processing pro-inflammatory cytokines to maturation 25] (Figure 2A). NLRP1 is composed of an N-terminal and release [22]. Activation of inflammatory caspase pyrin domain (PYD), a nucleotide-binding oligomeri- provides the first line of defense against infectious zation domain (NOD), a leucine-rich repeats (LRR), pathogens. Caspase-1 is activated in a multiprotein and a C-terminal caspase recruitment domain complex called the inflammasome in the canonical (CARD) [26]. The PYD is required for combining with pyroptosis pathway. The inflammatory caspase- ASC. NOD involves in adenosine triphosphate 4/5/11 do not need such molecular complex for their (ATP)-dependent activation of the signal. LRR is activation, which were shown to bind lipopolysac- responsible for ligand recognition and auto-inhi- charide (LPS) directly. Apoptotic caspases function bition. CARD takes part in pro-caspase-1 recruitment. predominantly to initiate and execute apoptosis. Anthrax lethal toxin, muramyl dipeptide, and Recent studies have shown that they can serve as the components of Toxoplasma gondii can activate NLRP1 proteases to cleave gasdermins for pyroptosis [27]. NLRP3 consists of an N-terminal PYD, a NOD, induction [16]. The details of each signaling pathway and an LRR, without C-terminal CRAD. The NLRP3 is of pyroptosis are discussed below. activated by various factors, including bacteria, viruses, fungi, uric acid, reactive oxygen species Canonical inflammasome pathway (ROS), adenosine triphosphoric (ATP), and The canonical inflammasome pathway was the endogenous damage signals [28]. Extracellular ATP first to be discovered. Inflammasomes are induces IL-1β secretion and caspase-1 activation by multi-protein complexes assembled in response to activating the P2X purinoreceptor 7 (P2X7) and pathogen-associated molecular patterns or inducing K efflux [29]. NLRC4 has an N-terminal non-pathogen-related damage-associated molecular CARD domain, a central NBD domain, and a patterns. Generally, inflammasomes are comprised of C-terminal LRR domain. NLRC4 responds to type III intracellular pattern recognition receptors (PRRs), secretory system proteins and flagellin [30]. AIM2 apoptosis-associated speck-like protein containing a holds a PYD domain and a DNA-binding HIN-200 caspase-recruitment domain (ASC), and inflam- domain that can sense bacteria- or viruses-derived matory caspases [23]. The most common PRRs include double-stranded DNA [31]. Pyrin has a PYD domain, nucleotide-binding oligomerization domain-like two B-boxes, and a C-terminal SPRY/PRY domain. receptors (NLRs, including NLRP1, NLRP3, and Pyrin mainly recognizes the inactivating modifica- NLRC4), absent in melanoma 2 (AIM2), and pyrin [24, Figure 2. Schematic illustration of the different pyroptosis pathways. (A) In the canonical inflammasome pathway, pathogen-associated molecular patterns or damage-associated molecular patterns like viruses, bacteria, toxins, ATP, or ROS stimulates inflammasome, which then activates caspas e-1 to cleave GSDMD for pore formation. (B) LPS from Gram-negative bacteria activates caspase-4/5/11 directly, followed by GSDMD cleavage to execute pyroptosis in the non-canonical inflammasome pathway. (C) Apoptotic caspases-mediated pyroptosis pathway can be engaged through mechanisms such as caspase-3/GSDME, caspase-8/GSDMC, caspase-6/GSDMB, and so on. (D) In the granzymes-mediated pathway, GZMA or GZMB derived from cytotoxic lymphocytes can cleave GSDMB or GSDME respectively for pore formation and pyroptosis. https://www.thno.org Theranostics 2022, Vol. 12, Issue 9 4313 tions of host Rho guanosine triphosphatases mediated cleavage of GSDME [39]. Another apoptotic caspase by various bacterial toxins or effectors [25]. Upon that can trigger pyroptosis is caspase-8, which can stimulation of PRRs, pro-caspase-1 is recruited induce the cleavage of GSDMD to elicit pyroptosis directly by CARD-carrying PRRs or indirectly via ASC during Yersinia infection [17, 40]. When transforming to assemble caspase-1-dependent inflammasomes, growth factor-β-activated kinase 1 is inhibited by the which is followed by caspase-1 activation through Yersinia effector YopJ, lysosome Rag-Ragulator self-cleavage. Active caspase-1 not only cleaves served as a platform for activating a Fas-associated inactive IL-1β and IL-18 precursors, but also cleaves death domain/receptor-interacting serine-threonine GSDMD to release GSDMD-NT for pore-formation, protein kinase 1/caspase-8 complex to trigger eventually leading to inflammatory responses and pyroptosis [41]. Besides, caspase-8 can also cleave pyroptosis [32]. The canonical inflammasome GSDMC, liberating the N-terminus of GSDMC to pathway-mediated pyroptosis mainly occurs in form pores in the cancer cell membrane [42]. In immune cells and serves as a host defense mechanism addition, Chao et al. showed that apoptosis-related against pathogen infection. caspase-3/6/7 cleaves GSDMB, thus removing the C-terminal repressor domain, to cause the release of Non-canonical inflammasome pathway the N-terminal effector domain, which perforates the The non-canonical inflammasome pathway is cell membrane and ultimately evokes cell pyroptosis independent of the classical inflammasome complex. [43]. Most Gram-negative bacteria activate the non-canoni- Granzymes-mediated pathway cal inflammasome pathway. Extracellular LPS can induce the expression of type I interferon, which then Recently, studies have shown that natural killer forms a feedback loop and activates type I interferon cells, cytotoxic T lymphocytes, or chimeric antigen receptor to induce caspase-11 expression [33, 34]. receptor T cells derived granzymes, which are Vacuolar Gram-negative bacteria release their LPS delivered by perforin into target cells, can cleave into the cytosol through vacuolar rupture triggered by specific gasdermin family members to induce cancer interferon-inducible guanylate-binding proteins. The cell pyroptosis (Figure 2D). Granzyme A (GZMA) is released LPS can directly bind to and activate the most abundant serine protease of the granzyme caspase-11, which then cleaves GSDMD to promote family, which has traditionally been recognized as a pyroptosis [35, 36] (Figure 2B). In human, caspase-4/5 mediator of cell death. However, there are many can be activated by intracellular LPS. Caspase-4/5/11 reports have shown that GZMA fails to kill target cells cannot cleave pro-IL-18 and pro-IL-1β directly, but K in vitro unless very high concentrations are used efflux caused by GSDMD -NT pores can activate [44-46]. Accumulating evidence now suggests the role NLRP3 and caspase-1, eventually leading to of GZMA in modulating inflammation, such as maturation and release of IL-18 and IL-1β [37]. In inducing the maturation and release of addition, Yang et al. demonstrated that cleavage of pro-inflammatory cytokines [47-49]. Pyroptosis, one the pannexin-1 channel and ATP release occur in a type of cell death that is accompanied by caspase-11-dependent manner upon LPS stimulation, pro-inflammatory cytokines release, may be which then activate ATP-gated ion channel P2X7, associated with GZMA. Recently, Zhou et al found ultimately resulting in K efflux and subsequent that GZMA derived from cytotoxic T lymphocytes NLRP3/caspase-1 activation in bone marrow-derived cleaves GSDMB to form pores in the membrane, macrophages [38]. Therefore, the activation of NLRP3 resulting in pyroptosis of GSDMB-expressing cancer inflammasome induced by the active caspase-11 is cells [50]. So, whether the GZMA can kill cancer cells required for IL-1β processing in the non-canonical through pyroptosis also depends on the expression of inflammasome pathway. GSDMB, which do not express in some human tissue and is absent in mouse. Natural killer cell-derived Apoptotic caspases-mediated pathway granzyme B (GZMB) can directly cleave GSDME at In addition to inflammatory caspase-1/4/5/11, the same site that is cleaved by caspase-3, leading to some apoptotic caspases can also trigger pyroptosis the release of the effector N-terminal, which (Figure 2C). Chemotherapy drugs can induce perforates the cell membrane [51]. GZMB induces caspase-3-mediated apoptosis, if the target cells GSDME-dependent pyroptosis in tumor targets both express GSDME, the activated caspase-3 can cleave directly by cleaving GSDME and indirectly by GSDME to induce pyroptosis, which switches the activating caspase-3. The direct cleavage of GSDME mode of cell death. Wang et al. found that cisplatin by GZMB provides a simple mechanism and pathway and other conventional chemotherapy drugs can for triggering inflammatory death. Caspase-resistant induce pyroptosis through caspase-3-mediated cancer cells should be susceptible to this direct https://www.thno.org Theranostics 2022, Vol. 12, Issue 9 4314 pathway, provided that the cancer cells express significantly reduce infarct size by inhibiting the GSDME. Granzymes-mediated cancer cell pyroptosis ATPase activity of NLRP3 [60, 61]. The small molecule may amplify the inflammatory response in the tumor 16673-34-0 prevents NLRP3 oligomerization in microenvironment (TME), thereby recruiting more cardiomyocytes and limits myocardial injury after immune cells for antitumor immunity. myocardial ischemia-reperfusion in the mouse model [62]. MCC950 is shown to inhibit NLRP3-induced Inhibiting pyroptosis to treat ASC oligomerization, by which reducing infarct size, inflammatory diseases improving cardiac remodeling, and preventing left ventricular dysfunction in a pig model of MI [63]. In normal physiology, moderate pyroptosis Colchicine acts upstream of NLRP3 to block the plays an important role in the host defense against opening of P2X7 channel and interfere with ASC pathogenic microorganisms [52, 53]. However, polymerization [64, 65]. Treatment with colchicine dysregulated inflammatory response and cell death successfully attenuates NLRP3 inflammasome caused by overactivated pyroptosis may be involved activity, improves cardiac function, and prolongs in the pathological progression of many diseases [54, survival after MI [66]. 55], especially inflammatory diseases. Herein, we mainly discuss the role and therapeutic potential of pyroptosis in inflammatory diseases, like Table 1. Potential strategies targeting pyroptosis to treat cardiovascular diseases cardiovascular diseases, liver diseases, and nervous system diseases. Targets Agents Disease model Findings Ref. NLRP3 INF4E IRI in mouse Reduces infarct size at 60 min [60] Cardiovascular diseases OLT1177 IRI in mouse Limits infarct size and preserves [61] left ventricular contractile function Cardiovascular diseases are the primary cause of 6673-34-0 IRI in mouse Limits the infarct size [62] MCC950 MI in pig Reduces infarct size and preserves [63] patient suffering and high mortality worldwide. cardiac function Recently, many studies have shown that pyroptosis is Colchicine MI in mouse Improves chronic cardiac function [66] and survival closely related to the occurrence and development of Melatonin Atherosclerosis in Reduces the atherosclerotic plaque [67] cardiovascular diseases, such as atherosclerosis, mouse in aorta ischemia-reperfusion injury (IRI), and myocardial PDA@M IRI in rat Decreases the infarct size [68] and improves the cardiac function infarction (MI). Caspase-1 VX-765 IRI in rat Reduces infarction and preserves [69] The pathogenesis of atherosclerosis involves ventricular function smooth muscle cell proliferation and migration, Besides the inhibitors that directly affect NLRP3, endothelial cell dysfunction, pro-inflammatory there are agents that can suppress the activity of cytokine secretion, and cell death [56]. Previous NLRP3 indirectly. Zhang et al. showed that the studies have illustrated that pyroptosis in macro- anti-inflammatory agent melatonin can prevent phages, endothelial cells, and smooth muscle cells are endothelial cell pyroptosis by regulating the signaling related to the progression of atherosclerosis [57]. Duewell et al. showed that cholesterol crystals can pathway of maternally expressed gene 3/miR-223/ NLRP3 in atherosclerosis [67]. Wang et al. showed activate caspase-1 through the NLRP3 inflammasome, that melatonin reduced cigarette smoke extract- which cleaves pro-IL-18 and pro-IL-1β to produce induced pyroptosis by inhibiting the ROS/NLRP3 their mature forms, resulting in inflammation and axis in atherosclerosis [70]. Liraglutide alleviates atherosclerosis formation [58]. NLRP3 inflammasome-mediated pyroptosis in H9c2 IRI involves different types of cell death, among cells, by regulating the sirtuin 1 (SIRT1)/NAPDH which pyroptosis is one of the commonly observed cell death modes. Lou et al. illustrated that microRNA oxidase 4/ROS pathway [71]. Wei et al. reported that a polydopamine-based biomimetic nanoplatform (miR)-424 is markedly upregulated in IRI conditions, (PDA@M) can inhibit pyroptosis to protect the which reduces the expression of cysteine-rich myocardium against IRI. PDA@M consists of a secretory protein LCCL domain-containing 2 and polydopamine core and a macrophage membrane results in the upregulation of caspase-1, IL-18, and IL-1β in cardiac pyroptosis under IRI [59]. shell, to achieve site-specific antioxidative efficacy [68]. The results demonstrated that PDA@M targets Since pyroptosis is involved in the occurrence and progression of cardiovascular diseases, many the infarcted myocardium to suppress the NLRP3/ caspase-1 pathway, thus exerting antioxidative and strategies have been developed to target pyroptosis antipyroptosis functions, suggesting that it may serve for the treatment of these diseases (Table 1, Figure 3). as a potential therapeutic agent for IRI. There are numerous inhibitors of NLRP3 Caspase-1 inhibitors can also inhibit pyroptosis, inflammasome, such as INF4E and OLT1177, when given in mouse model of IRI, the inhibitors and thus, serve to be useful in the treatment of https://www.thno.org Theranostics 2022, Vol. 12, Issue 9 4315 cardiovascular diseases. For example, the caspase-1 NLRP3 inflammasome induces caspase-1 cleavage, inhibitor VX-765 has been shown to produce a and ultimately leads to pyroptosis at the NAFL stage sustained reduction in myocardial infarct size and [76]. The inflammation or fibrosis induced by facilitate preservation of ventricular function in a pyroptosis is more serious at the stage of NASH [74, pre-clinical model of IRI treated with a P2Y receptor 75]. A study proved that GSDMD-NT was antagonist [69]. Moreover, VX-765 was able to reduce upregulated in NAFL and showed higher levels in myocardial infarction in a model of IRI, NASH [77]. GSDMD knockout mice fed with demonstrating that caspase-1 inhibition is an effective methionine-choline deficiency showed milder method for treating pyroptosis-triggered cardiovas- steatosis and inflammation compared with WT mice. cular diseases [72]. These results indicated that pyroptosis executor GSDMD-NT is responsible for the pathogenesis of Liver diseases NAFLD by regulating adipogenesis and secreting Liver diseases are serious problems that inflammatory cytokines [77]. endanger human health worldwide. Recently, studies Due to the serious inflammatory response and have demonstrated that pyroptosis is responsible for liver damage caused by the excessive intake of the progression of liver diseases. When the intestinal alcohol, alcoholic liver disease presents a very high flora is out of balance, the gut microflora can enter the mortality worldwide. However, owing to our poor liver through the intestine-liver axis, which then understanding of the molecular mechanisms triggers pyroptosis in liver cells [73]. underlying the condition, currently, there is still no Non-alcoholic fatty liver disease (NAFLD) has effective treatment strategy for it. It is well established become a serious health problem owing to its high that excessive uptake of alcohol is often related to incidence and high risk of cirrhosis. The roles of cell different forms of cell death, including pyroptosis. necrosis and apoptosis in NAFLD have been Heo et al. discovered that alcohol can decrease the emphasized, but it has only recently been recognized expression of miR-148a through forkhead box O1 that pyroptosis may also play an important role in this (FoxO1) in hepatocytes, which leads to condition. NAFLD is further categorized into overexpression of thioredoxin-interacting protein and non-alcoholic fatty liver (NAFL) and non-alcoholic activation of NLRP3 inflammasome, eventually steatohepatitis (NASH). NAFL is characterized by the inducing pyroptosis in hepatocytes [78]. By reducing accumulation of triglycerides in hepatocytes, while caspase-1-induced pyroptosis, selenium-enriched S. NASH involves massive cell damage, inflammatory platensis displays a protective role in chronic cell infiltration, and hepatocyte expansion [74, 75]. alcohol-induced liver injury [79]. After sensing lipotoxicity-associated ceramide, the Figure 3. Potential strategies targeting pyroptosis for the treatment of cardiovascular diseases. https://www.thno.org Theranostics 2022, Vol. 12, Issue 9 4316 Table 2. Targeting the signaling pathways of pyroptosis to treat liver diseases Targets Agents Disease Mechanism Ref. NLRP3 MCC550 Liver fibrosis Reduces expression of IL-1β and IL-18, and suppresses neutrophil infiltration and [82] hepatic cell death P2X7 inhibitor Liver disease Prevents ATP-mediated activation of NLRP3 [83] Silybin NAFLD Inhibits assembly of NLRP3 inflammasome [84] Dihydroquercetin Alcoholic liver disease Decreases expression of P2X7and NLRP3, and suppresses cleavage of caspase-1 [85] Liraglutide NAFLD Inhibits the NLRP3 inflammasome and pyroptosis activation [86] Downstream of NLRP3 Caspase-1 inhibitor Liver disease Prevents caspase-1-dependent cell death [87] Rosiglitazone NAFLD Inhibits production of hepatic IL-18 [88] IL-1β receptor antagonist Liver fibrosis Block IL-1-mediated inflammation in selective liver fibrotic disease [89] Additionally, liver inflammation has been effect of GSDMD inhibitors requires further shown to be related to pyroptosis during the investigation for the treatment of various liver development of liver fibrosis. The fibrosis-related diseases in the future. proteins are mainly derived from hepatic stellate cells, Nervous system diseases which get activated and produce collagen through Emerging studies imply that pyroptosis may be pyroptosis [80]. In addition to hepatic stellate cells, involved in the pathology of nervous system diseases infiltrated eosinophils have been shown to induce such as ischemic stroke, Parkinson’s disease (PD), and secretion of pro-inflammatory cytokines IL-18 and Alzheimer’s disease (AD). AD is a common IL-1β, or even pyroptotic cell death of hepatocytes, neurodegenerative disease that is characterized by leading to liver fibrosis. The caspase-1 inhibitors dementia and cognitive decline. The main significantly suppress this process, further suggesting pathological features of AD are β-amyloid protein that pyroptosis plays a crucial role in eosinophil- (Aβ) deposition in the extracellular neuritic plaque, induced hepatic fibrosis [81]. neurofibrillary tangles due to aggregation of The above studies indicate that inhibiting abnormally phosphorylated tau protein, vascular pyroptosis might be a potential therapeutic strategy amyloidosis, and neuronal death in the brain. Aβ or for liver diseases. So, there are many researches hyperphosphorylated tau can activate NLRP1, AIM2, targeting pyroptosis for the treatment of liver and NLRP3 inflammasome, eventually resulting in diseases, mainly involving two strategies: direct pyroptosis of neurons both in vitro and in vivo [90, 91]. inhibition of NLRP3 inflammasome and restraining of PD is another neurodegenerative disorder downstream signaling pathways of the NLRP3 characterized by the loss of dopaminergic neurons in inflammasome (Table 2). Qu et al. [82] demonstrated the midbrain. Accumulating evidence demonstrates that MCC950, which is known as an NLRP3 inhibitor, the involvement of pyroptosis in PD. miR-135b significantly alleviates bile duct ligation-induced liver alleviates 1-methyl-4-phenylpyridinium-induced PD fibrosis by reducing IL-18 and IL-1β expression, and in an in vitro model by suppressing FoxO1-induced suppressing neutrophil infiltration and hepatic cell NLRP3 inflammasome activation and pyroptosis, death. P2X7 inhibitors prevent ATP-mediated which suggests that pyroptosis contributes to PD activation of NLRP3 [83]. In addition to these progression [92]. Moreover, the long non-coding RNA inhibitors, some herbal extracts and ingredients can HOTAIR facilitates NLRP3-mediated pyroptosis to inhibit signaling pathways of pyroptosis and reduce aggravate neuronal damage in PD [93]. Taken liver damage. Zhang et al. showed that silybin together, these studies indicate that inhibiting significantly inhibits the assembly of NLRP3 pyroptosis might be a novel therapeutic strategy for inflammasome in mice with NAFLD [84]. A study has PD. demonstrated that dihydroquercetin can decrease the In addition to AD and PD, recent studies have expression of P2X7 and NLRP3, and subsequently demonstrated that pyroptosis of microglia or neurons suppress cleavage of caspase-1 in an animal model of participates in ischemic stroke. Yan et al. showed that alcoholic liver steatosis [85]. Liraglutide, an analog of neuronal pyroptosis is conducive to early ischemic glucagon-like peptide-1, has been shown to inhibit injury through the SIRT1-ROS-tumor necrosis factor NLRP3 inflammasome-mediated pyroptosis and (TNF) receptor-associated factor 6 signaling pathway attenuate mitochondrial dysfunction, which [94]. Moreover, neuron pyroptosis may cause significantly ameliorates NASH [86]. mitochondrial dysfunction, eventually leading to The potential effects of caspase-1 [87], IL-18 [88], increased ROS levels and aggravated ischemic and IL-1β [89] inhibitors have been studied to target injuries. In addition, the diffusion of intracellular the downstream signaling pathways of the NLRP3 inflammatory factors is facilitated by GSDMD- inflammasome. GSDMD is the final executor, but mediated pyroptosis in astrocytes, microglia, and there are very few studies targeting it. The potential https://www.thno.org Theranostics 2022, Vol. 12, Issue 9 4317 infiltrating macrophages, which promotes ischemic all gasdermins can serve as the executors. Pyroptosis brain injury [95-97]. plays a vital role in tumor development and As pyroptosis plays a prominent role in antitumor immunity, by acting as a double-edged pathological process of nervous system diseases, sword that can show both tumor-promoting and many small-molecule inhibitors have been developed tumor-suppressing effects. On the one hand, to target pyroptosis-related signaling pathways for long-term chronic pyroptosis of cancer cells triggered treating these diseases (Figure 4). Inflammasome by the adverse TME is more likely to promote cancer family members have attracted the most attention as progression. Chronic pyroptosis triggers the starting point of pyroptosis. MCC950 is a pro-inflammatory cytokines that facilitate the well-known selective inhibitor of NLRP3, which can formation and maintenance of an inflammatory alleviate the pathological progression of various microenvironment for tumor growth. It has been nervous system diseases, such as AD [98], PD [99], reported that GSDME-mediated pyroptosis promotes and ischemic stroke [94]. Furthermore, salidroside can the development of colitis-associated colorectal cancer suppress NLRP3-dependent pyroptosis to ameliorate by releasing high-mobility group box protein 1, which PD [100]. In addition, as an antagonist of cyclic induces tumor cell proliferation and the expression of GMP-AMP synthase and AIM2 inflammasome, A151 proliferating nuclear antigen through the ERK1/2 prevents pyroptosis of microglia and reduces infarct pathway [104]. Chronic inflammation and pyroptosis volume, ultimately relieving neurodeficits after also involves the development of asbestos-associated ischemic stroke [96]. mesothelioma [105]. On the other hand, acute and Downstream of the inflammasome, active immense activation of pyroptosis results in numerous caspase can cleave gasdermin protein and drive immune cells infiltration, which not only induces pyroptosis. Hence, caspase is another attractive target massive cancer cell death but also activates antitumor for inhibiting pyroptosis. For instance, as a caspase-1 immunity to repress tumor growth [106]. The inhibitor, VX-765 can reduce pyroptosis to alleviate antitumor immunity of pyroptosis involves many injury after AD [101] and stroke [102]. Gasdermin respects, which starts with the release of proteins are the final executors of pyroptosis, and damage-associated molecular patterns and there are drugs that target gasdermins directly. Han et inflammatory cytokines that directly modulates the al. showed that necrosulfonamide, which can inhibit innate immune response, to enhance the recruitment GSDMD oligomerization by binding to the amino acid of adaptive immune cells along with increased of C191, suppresses Aβ-triggered neuronal pyroptosis antigen presentation, resulting in extensive immune in vivo [91]. activation. The released inflammatory cytokines IL-1β can induce dendritic cell (DC) maturation, activate CD8 T cells, and inhibit the differentiation of immunosuppressive T regulatory cells [107]. IL-18 plays critical role in natural killer (NK) cell recruitment and activation, as well as Th-1 polarization [108]. All of these alter the immunosuppressive microenvironment and increase tumor-infiltrating lymphocytes. Thus, inducing acute and massive cancer cell pyroptosis is a potential strategy for tumor treatment. Herein, we summarize the latest progress in pyroptosis-based cancer therapy (Table 3), and the related immune methods are also summarized (Table 4). Figure 4. Therapeutic strategies for treating nervous system diseases by targeting pyroptosis. GSDMD-mediated pyroptosis for cancer therapy GSDMD was the first gasdermin discovered to Inducing cancer cell pyroptosis for cancer be associated with pyroptosis. Shi and Kayagaki et al. therapy showed that GSDMD participates in both canonical and non-canonical pyroptosis [8, 36]. To date, it has The mechanisms of pyroptosis in cancer cells been found that both inflammatory caspase-1/4/5/11 and immune cells are different. In cancer cells, and apoptotic caspase-8 can cleave GSDMD to induce inflammasome is not necessary for pyroptosis pyroptosis. induction and other active proteases except caspases are able to cleave gasdermins [103], in which almost https://www.thno.org Theranostics 2022, Vol. 12, Issue 9 4318 Table 3. Inducing cancer cell pyroptosis for cancer therapy Strategy Cancer types Mechanism Ref. GSDMD-mediated pyroptosis for cancer therapy Simvastatin NSCLC NLRP3/caspase-1/GSDMD [109] a-NETA Ovarian cancer Caspase-4/GSDMD [110] Lip-MOF Cervical cancer Caspase/GSDMD [111] TBD-R Breast cancer, cervix carcinoma, and glioblastoma ROS/caspase-1/GSDMD [112] VTPA Breast cancer Lysosomal rupture and ROS/NLRP3/caspase-1/GSDMD [113] AMPCP Melanoma ATP/NLRP3/caspase-1/GSDMD [114] GSDME-mediated pyroptosis for cancer therapy Paclitaxel, cisplatin Lung cancer Caspase-3/GSDME [115] Lobaplatin Colon cancer ROS and pJNK/ Bax/ Cytochrome c/Caspase-3/9/GSDME [116] As2O3-NPs Hepatocellular carcinoma Caspase-3/GSDME [117] DAC+LipoDDP Breast cancer Caspase-3/GSDME [118] DOX/JQ1-IBRN Breast cancer Caspase-3/GSDME [119] 2+ BNP Breast cancer Ca /Cytochrome c/ Caspase-3/GSDME [120] NCyNP Breast, lung, and cervical cancers. CyNH /Cytochrome c/ Caspase-3/GSDME [121] MCPP Colon cancer ROS/ Caspase-3/GSDME [122] GSDMC/B/A-mediated pyroptosis for cancer therapy α-KG Cervical cancer and melanoma ROS/DR6/Caspase-8/GSDMC [123] GSDMB Colon cancer GZMA/GSDMB [50] Phe-BF3+NP-GA3 Cervical and breast cancer Phe-BF3/GSDMA3 [124] Table 4. Summary of the strategies that induce pyroptosis for cancer therapy related to immune methods Strategy Cancer types Immune response Ref. AMPCP Melanoma Remodels ITME and sensitizes tumors to anti-PD-L1 therapy [114] DAC+LipoDDP Breast cancer Secrets IL-1β and HMGB1, induces the DCs maturation, and increases presence of CTLs [118] DOX/JQ1-IBRN Breast cancer Modulates ITME, JQ1 blocks PD-L1 mediated immune evasion, and reduces Tregs [119] BNP Breast cancer Secrets pro-inflammatory factors to induce DC maturation and T cell activation in TDLNs [120] NCyNH2, NCyNP Breast, lung, and cervical cancers. Promotes CTLs infiltration in TME and DCs maturation in TDLNs, synergizes with αPD-1 to [121] induce antitumor immunity and generates an immune memory effect MCPP Colon cancer Initiates adaptive immunity, boosts the PD-1 blockade efficiency, generates immunological memory, [122] and prevents tumor recurrence. GSDMB Colon cancer Promotes CTL-mediated tumor clearance when combined with αPD-1 [50] + + Phe-BF3+NP-GA3 Cervical and breast cancer Increases CD4 , CD8 , and NK cell populations, decreases Tregs and myeloid-derived suppressor [124] cell populations Simvastatin is a well-established anti-hyperlipi- current therapies fail to eradicate colorectal CSCs demic drug that inhibits 3-hydroxy-3-methylglutaryl- effectively. The phenotype of CSCs and their coenzyme A reductase to reduce cholesterol levels. resistance to chemotherapy drugs are related to C-X-C Recently, Wang et al. demonstrated that simvastatin motif chemokine receptor 4 (CXCR4) overexpression can activate NLRP3-caspase-1 pathway to induce in colorectal cancer. Based on this fact, Serna et al. pyroptosis in non-small cell lung cancer (NSCLC) cell constructed a self-assembling toxin nanoparticle, in lines and mouse models [109]. Inhibition of pyroptosis which the CXCR4 ligand T22 was fused with the reduced the effects of simvastatin on cancer cell therapeutic material diphtheria toxin (DITOX) viability and mobility. These data suggest that the (T22-DITOX-H6) [125]. T22 endows the specificity of anti-hyperlipidemic drug simvastatin may serve as a toxin nanoparticles to target and kill CXCR4 -CSCs. novel therapeutic agent for NSCLC via pyroptosis. Protein synthesis was hindered by DITOX, which Qiao et al. reported that 2-(anaphthoyl) ethyl- eventually led to pyroptotic cell death. T22- trimethylammonium iodide (a-NETA) induces DITOX-H6 also showed greater inhibition of tumor pyroptosis of epithelial ovarian cancer cells via the growth compared to that in the control group in vivo. caspase-4/GSDMD pathway [110]. The cytotoxic Thus, owing to the specific CXCR4 targeting and effect of a-NETA was strongly blocked by knockdown effective cytotoxicity of DITOX, this nanoparticle can of either GSDMD or caspase-4 in ovarian cancer cells. efficiently eliminate apoptotic-resistant CXCR4 Treatment with a-NETA significantly decreased the colorectal CSCs through pyroptosis, demonstrating a size of the epithelial ovarian tumors in vivo. These promising method for colorectal cancer therapy. results imply that a-NETA may be a promising To a certain degree, cellular survival depends on antitumor molecule for epithelial ovarian cancer ion homeostasis. Altering the concentration of a therapy through pyroptosis. specific ion is usually used as a strategy to trigger Owing to their high self-renewal and clonogenic different forms of cell death. Nevertheless, because capacity, cancer stem cells (CSCs) are regarded as the the ion balance is tightly regulated by cells, the root of tumors. However, due to drug resistance, the investigation of certain ions influence on cells in a https://www.thno.org Theranostics 2022, Vol. 12, Issue 9 4319 controlled manner has been obstructed. Specific expression of caspase-1 and GSDMD in 4T1 cells after hybrid metal-organic framework (MOF) nanoparticles different treatments. The results showed that serve as a promising candidate for transporting ions caspase-1 activation and GSDMD cleavage were stealthily into cells and releasing an overdose of ions enhanced upon photodynamic therapy with TBD-R. in a controlled manner. Ploetz et al. designed a Together, this study provides a pyroptosis-based and lipid-coated MIL-100 consisting of ferric ions and photo-activated powerful approach for cancer cell trimesic acid (Lip-MOFs), to transport high amounts removal. of iron ions into cells [111]. The coated lipid not only The lack of tumor-specific pyroptotic agents in prevents cellular recognition of the ions on the MOF vivo impedes the actual applications of pyroptosis- surface, but also facilitates cellular uptake via based cancer therapy. Nadeem et al. reported the endocytosis. After uptake, the Lip-MOFs transfer to development of a virus-spike tumor-activatable lysosomes and then degrade into trimesic acids and pyroptotic agent (VTPA) for cancer-specific therapy 3+ Fe ions by means of pH-dependent and [113]. The VTPA consists of a manganese dioxide cysteine-involved reduction. Lysosomal rupture and spiky structure and an organosilica-coated iron oxide subsequent pyroptosis are triggered by large amounts nanoparticle (IONP) core (Figure 5A). Protrusions 3+ of Fe ions. The reduced expression of full-length facilitate lysosomal rupture, following which the GSDMD and increased release of IL-1β observed in tumor overexpressed glutathione (GSH) triggers the this study demonstrated that pyroptosis was the degradation of VPTA to release Mn ions and IONPs dominant cell death mode. This protective ion for rapid and persistent ROS generation, which delivery and controlled release to cells may pave the synergistically activates the NLRP3/caspase-1/ way for future applications of similar nanostructures GSDMD signaling pathway for pyroptosis (Figure that may be used to eliminate tumor cells in the acidic 5B). Moreover, VTPA showed excellent tumor growth tumor environment by means of pyroptosis and elicit inhibition via pyroptosis in vivo (Figure 5C). This an immune response simultaneously. In addition, iron study provides a tumor-activatable and was also reported to induce a GSDME-dependent nanostructure-dependent pyroptotic agent, pyroptosis [126]. Iron has been shown to trigger highlighting a novel direction for the development of oxidative stress by elevating ROS. On the one hand, next-generation cancer-specific pyroptotic ROS can activate the NLRP3 inflammasome and then nanomedicine in the future. induce GSDMD-dependent canonical pyroptosis; on With limited T-cell responses, it is challenging to the other hand, iron enhanced ROS can cause the overcome innate or adaptive resistance to immune oxidation of the mitochondrial outer membrane checkpoint inhibitor therapy in solid tumors. As an protein Tom20. Oxidized Tom20 recruits Bax to inflammatory form of PCD, pyroptosis is a promising mitochondria, which promotes the release of strategy for enhancing cancer immunotherapy. Xiong cytochrome c to activate caspase-3, eventually et al. designed a GSH-responsive nanomicelles triggering pyroptosis by inducing GSDME cleavage. prodrug, composed of the adenosine inhibitor α, Hence, iron can induce GSDMD- or β-methylene adenosine 5’ diphosphate (AMPCP) and GSDME-mediated pyroptosis depending on the cell the epigenetic modulator γ-oryzanol (Orz) for tumor context. therapy, which they termed as AOZN (Figure 5D) As an inflammatory form of PCD, pyroptosis is a [114]. When AOZN reaches the tumor site, high GSH promising strategy for fighting against cancer. In an in the TME triggers AMPCP and Orz release. The attempt to reduce side effects and achieve DNA methyltransferase inhibitor Orz can upregulate non-invasiveness, Wu et al. designed a series of the expression of GSDMD, AMPCP acts as an membrane-anchoring photosensitizers to induce ecto-5′-nucleotidase inhibitor to reduce adenosine pyroptosis for cancer cell ablation [112]. 1,1,2,2- levels and increase ATP accumulation, subsequently tetraphe-nylethene-benzo[c] [1,2,5] thiadiazole-2- initiating NLRP3 inflammasome assembly and (diphenyl methylene) malononitrile (TBD) and phenyl caspase-1 activation. Active caspase-1 directly cleaves rings (TBD-R) were conjugated with cationic chains to GSDMD and induces pyroptosis in tumor cells obtain aggregation-induced emission photosensi- (Figure 5E). Moreover, Orz and AMPCP tizers. Upon light irradiation, the produced ROS led synergistically combat the immunosuppressive TME to direct damage to the cell membrane and ablation of (ITME). After treatment with AOZN, a more marked cancer cells. Along with the increase of the increase in CD8- and CD4-positive T cells was membrane-anchoring capability of TBD-R, pyroptosis observed in the tumor tissue, while there is a gradually became the dominant cell death mode. To significant decrease in the frequencies of regulatory T uncover the mechanism of TBD-R-initiated pyroptotic cells and CD8 T cell exhaustion in the AOZN group, cell death, the study also evaluated the protein as compared to those in the control group. https://www.thno.org Theranostics 2022, Vol. 12, Issue 9 4320 Additionally, Orz can sensitize tumors to cancers and is mainly activated by apoptotic caspase-3 anti-programmed death-ligand 1 (PD-L1) therapy by and caspase-8. Chemotherapy can activate caspase-3 increasing the expression of PD-L1 (Figure 5F). In to trigger pyroptosis in GSDME-expressing cancer summary, this work proposes a promising strategy to cells [16, 39]. Zhang et al. showed that the enhance cancer immunotherapy and overcome the chemotherapeutic drug paclitaxel can trigger resistance to immune checkpoint blockers. pyroptosis in A549 cells, which is closely related to the levels of activated caspase-3 and GSDME-NT [115]. GSDME-based pyroptosis for cancer therapy Compared to paclitaxel, cisplatin induced more The expression of GSDME varies in different severe pyroptosis in NSCLC cells, indicating that Figure 5. GSDMD-mediated pyroptosis for cancer therapy. (A) Schematic presentation of the designed virus-spike tumor-activatable pyroptotic agent (VTPA). (B) The molecular mechanism of VTPA triggered pyroptosis in tumor cells. (C) Changes in the tumor volume after different treatments. (D) Schematic illustration of designed nanomicelles loaded with AMPCP and Orz (AOZN) for cancer immunotherapy. (E) The mechanism of pyroptosis induced by AOZN. (F) Tumor growth curves after different treatments. Adapted with permission from [113], copyright 2021 John Wiley and Sons, and [114], copyright 2021 John Wiley and Sons. https://www.thno.org Theranostics 2022, Vol. 12, Issue 9 4321 cisplatin may have more advantages than other drugs inhibitor, resulted in the up-regulation of DFNA5 for the treatment of tumors with high GSDME expression. Subsequently, cisplatin-loaded expression. In addition to cisplatin, lobaplatin is one nanoliposome (LipoDDP) was used to activate of the third-generation antitumor platinum that has caspase-3 and induce pyroptosis in DAC-treated stronger antitumor effects but fewer side effects. tumor cells (Figure 6A). Based on its performance in However, the inflammatory characteristics of terms of antitumor activities and metastasis lobaplatin in tumor treatment have not been reported. inhibition, this combined strategy triggered the Yu et al. showed that lobaplatin induced ROS immunological effects of chemotherapy and provided elevation and c-Jun N-terminal kinase phosphoryla- a novel insight into tumor immunotherapy (Figure tion in HT-29 and HCT116 cells, which further recruit 6B-C). Bax to the mitochondria, and thereby, stimulate the Residual microscopic lesions after surgery and release of cytochrome c, followed by caspase-3/9 the ITME contribute to a high rate of post-operative activation and GSDME cleavage, eventually tumor recurrence and metastasis (TRM). Drug-loaded triggering pyroptosis [116]. This study showed that scaffolds have the potential to inhibit TRM, but the GSDME-mediated pyroptosis is a novel mechanism actual therapeutic effects are limited by the ITME and for eradicating cancer cells using lobaplatin, which is untargeted toxicity from non-selective drug release. of great significance for clinical applications. Zhao et al. constructed an implantable bio-responsive In addition to classical chemotherapy drugs, nanoarray (IBRN) to reprogram the ITME and achieve arsenic trioxide (As O ) can accelerate the accurate tumor targeting in a controlled manner, for 2 3 differentiation of viable cancer cells and reduce the effective post-operative tumor therapy and TRM risk of metastasis, which partly achieves better prevention. The chemotherapeutic DOX and treatment responses with lower recurrence rates than epigenetic modulator JQ1 are packaged into traditional drugs. However, it is challenging to realize hyaluronic acid-modified polydopamine effective As O accumulation inside a solid tumor nanoparticles, which are then linked by a 2 3 with few systemic toxicities. To address this issue, Hu ROS-responsive linker to obtain a tumor-targeted et al. designed a triblock copolymer monomethoxy nanoarray loaded with another part of JQ1 (polyethylene glycol)-poly (d, l-lactide-co-glycolide)- (DOX/JQ1-IBRN) (Figure 6D). Upon reaching the poly (l-lysine) (mPEG-b-PLGA-b-PLL) nano-drug tumor site, high H O triggers the release of JQ1 and 2 2 system to deliver As O (As O -NPs). After the DOX, which realize ITME modulation and induce 2 3 2 3 As O -NPs are internalized by tumor cells, the As O GSDME-dependent pyroptosis, further eliciting 2 3 2 3 is released into the cytoplasm and GSDME is cleaved antitumor immunity and wiping out the residual following caspase-3 activation. The cleaved GSDME tumor completely [119]. The results showed that N-domains form membrane pores, eventually leading DOX/JQ1-IBRN inhibited post-surgical TRM and to pyroptosis. In vivo antitumor study showed that prolonged survival in tumor models with low As O moderately inhibited tumor growth, while toxicity. In summary, IBRN realizes accurate tumor 2 3 As O -NPs substantially reduced tumor growth. pyroptosis and ITME conversion to activate antitumor 2 3 As O -NPs treatment resulted in an increase in the immunity, for effective and safe prevention of TRM, 2 3 protein levels of cleaved caspase-3 and GSDME-NT, thus providing novel insights for post-operative with a decrease in those of Dnmt1, Dnmt3a, and treatment. Dnmt3b, thus uncovering the mechanism of the Pyroptosis is considered an excellent choice to antitumor activity of As O -NPs [117]. These data promote the immune response for cancer therapy, 2 3 provide a new vision and strategy for future because of its pro-inflammatory characteristics. Zhao hepatocellular carcinoma therapy based on pyroptosis et al. designed a biomimetic nanoparticle (BNP) by mediated by As O . fusing a breast cancer membrane shell onto a PLGA 2 3 As mentioned above, the expression of GSDME polymeric core loaded with indocyanine green and in cancer cells varies. It is silenced in some types of DAC, for photo-activated cancer cell pyroptosis and tumors due to the hypermethylation of the cancer immunotherapy. Due to the homing capability GSDME/DFN59 gene; owing to this, of the cancer cell membrane, BNP can effectively GSDME-mediated pyroptosis is absent in these accumulate in the tumor site with low tumors. Fan et al. developed a strategy of combining immunogenicity. The loaded indocyanine green can chemotherapy with DNA demethylation to trigger perforate the tumor cell membrane and induce a 2+ cancer cell pyroptosis, which amplifies the immune sudden increase in cytoplasmic Ca through effect to further eliminate tumors via immune therapy near-infrared (NIR) irradiation, which activates [118]. Pretreatment of tumor cells with decitabine caspase-3 by promoting the release of cytochrome c. (DAC), a commonly used DNA methyltransferase Meanwhile, DAC inhibits DNA methylation, which is https://www.thno.org Theranostics 2022, Vol. 12, Issue 9 4322 followed by upregulation of GSDME, eventually nodes, compared to those upon carrying out other causing pyroptosis. In vivo, the primary and distant treatments, indicating that photo-activated pyroptosis tumor growth was significantly repressed within 28 further induces inspiring antitumor immunity for days of using this strategy. After BNP treatment plus cancer therapy [120]. Together, BNP provides a novel photo-activation, a high percentage of CD8 T cells strategy for photo-activated cancer cell pyroptosis and CD4 T cells were detected in distant tumors and and robust solid tumor immunotherapy with high spleens, and a high rate of mature DCs were detected compatibility. in the primary tumor and tumor-draining lymph Figure 6. GSDME-mediated pyroptosis for cancer therapy. (A) Schematic illustration of the demethylation and immune activation process mediated by decitabine and LipoDDP + + + + + + via pyroptosis. (B) Quantification of CD4 and CD8 T cell-gating on CD3 cells in the tumors. (C) Statistical analysis of CD80 CD86 cell-gating on CD11c cells within tumor-draining lymph nodes. (D) Illustration of the DOX/JQ1-IBRN for post-surgical tumor treatment, involving pyroptosis of tumor cells, conversion of the ITME, and cascade activation of immunity. Adapted with permission from [118], copyright 2019 ACS, and [119], copyright 2020 John Wiley and Sons. https://www.thno.org Theranostics 2022, Vol. 12, Issue 9 4323 Figure 7. GSDMC/B-based pyroptosis for cancer therapy. (A) The working model of α-KG-induced pyroptosis via GSDMC. Adapted with permission from [123], copyright 2021 Springer Nature. (B) Cytotoxic lymphocyte-derived GZMA cleaves GSDMB in cancer cells to perforate the cell membrane and induce pyroptosis. Pyroptosis can effectively eradicate cancer cells GSDMC/B/A-related pyroptosis for cancer by boosting anticancer immunity; however, due to its therapy non-selectivity, most of the current pyroptosis In addition to GSDME and GSDMD, the inducers may cause severe side effects in cancer N-terminal domain of GSDMC/B/A also has the therapy. Wang et al. first reported that the NIR capacity to form pores in the cell membrane, to fluorophore-based hemicyanine CyNH can kill execute pyroptosis. Hou et al. showed that nuclear cancer cells and boost antitumor immunity by PD-L1 (nPD-L1) switches TNF-α-induced apoptosis to inducing pyrolysis. To realize the tumor-specificity of GSDMC-mediated pyroptosis in cancer cells [42]. CyNH , cancer cells high expressing NAD(P)H: Under hypoxic stress, p-Stat3 interacts with PD-L1 quinone oxidoreductase isozyme 1 (NQO1)-respon- and promotes its nuclear translocation, which sive CyNH (NCyNH ) were designed to trigger 2 2 transcriptionally activates GSDMC expression. After pyroptosis and further activate systemic antitumor TNF-α treatment, active caspase-8 cleaves GSDMC to immunity. In addition, NCyNH was further release its N-terminal domain, which forms pores on encapsulated in PEG-b-PLGA as a theranostic the cell membrane, eventually inducing pyroptosis. In nanocarrier (NCyNP) for systemic administration and addition, nPD-L1-switched pyroptosis is required for fluorescence imaging in vivo. NCyNPs combined with tumor necrosis in vivo. In brief, this study found a anti-programmed death-1 (PD-1) enhance the novel function of PD-L1 and identified that antitumor effect and prevent tumor recurrence by caspase-8/GSDMC mediates the pyroptosis pathway producing powerful memory efficacy [120]. Hence, in cancer cells, which facilitates tumor necrosis. the NIR fluorophore-based CyNH may represent a Metabolic homeostasis and metabolites affect novel theranostic agent for initiating tumor cell fate. α-ketoglutarate (α-KG) is an essential pyroptosis selectively and triggering immunotherapy metabolite in the tricarboxylic acid cycle that plays efficiently. To achieve higher tumor specificity, Xiao important roles in many physiological processes, such et al. designed a TME reactive ROS/GSH as oxidative stress reduction and cell death. dual-responsive nano-prodrug loaded with Nevertheless, the role of α -KG in pyroptosis remains photosensitizer purpurin 18 and paclitaxel (MCPP) to unknown. Zhang et al. demonstrated that dimethyl induce GSDME-mediated pyroptosis in cancer cells α-KG can pass through the cell membrane and induce specifically. Upon laser irradiation, ROS produced by the oxidation and endocytosis of death receptor 6 photosensitizer purpurin 18 realizes controlled (DR6) by elevating ROS levels [123]. After DR6 release and triggers cancer cell pyroptosis with internalization, both pro-caspase-8 and GSDMC are paclitaxel via chemo-photodynamic therapy. Pyrop- recruited to the DR6 receptosome, where active totic cancer cells further initiate adaptive immunity caspase-8 cleaves the GSDMC, finally resulting in and boost immune checkpoint blockade efficiency to pyroptosis (Figure 7A). α-KG-induced pyroptosis has prevent tumor growth and recurrence [122]. This been shown to be sufficient for inhibiting tumor study not only provides a highly efficient strategy to growth and metastasis in vivo. Fascinatingly, in an induce pyroptosis in tumor cells specifically, but also acidic environment, α-KG can be reduced to resolves a challenge in immune checkpoint blockade L-2-hydroxyglutarate (L-2HG) by the metabolic via pyroptosis. https://www.thno.org Theranostics 2022, Vol. 12, Issue 9 4324 enzyme malate dehydrogenase 1, which further the role of inflammatory caspases (caspases- boosts ROS and promotes pyroptosis. Treatment with 1/4/5/11) in pyroptosis. Afterwards, researchers lactic acid produces more L-2HG because of the have found that apoptotic caspases (caspases-3/6/8) improved acidic environment, which turns are also involved in the process of pyroptosis. pyroptosis-resistant cancer cells into pyroptosis- Moreover, recent studies have shown that sensitive cancer cells. Collectively, this study links GZMA/GZMB can trigger pyroptosis as well as metabolites with the pyroptosis pathway and caspases. These studies renovate our understanding illustrates how α-KG triggers DR6 endocytosis to of pyroptosis. Future research will continue to update bring about caspase-8/GSDMC-mediated pyroptosis, the novel and precise activation modes of pyroptosis, and thus, has application in cancer therapy. for instance, which caspases or other factors mediate During the period when apoptosis was consi- the cleavage of the GSDMA. dered the dominant form of PCD, granzymes were Generally, GSDMD cleavage by caspase-1 via the thought to kill target cells by means of apoptosis. canonical inflammasome pathway plays an important However, the discovery of pyroptosis has updated role in host defense against pathogen infections. our understanding of PCD. It is important to explore However, excessive inflammatory responses and cell whether gasdermin proteins respond to granzymes death caused by pyroptosis may be involved in and induce pyroptosis. Zhou et al. demonstrated that various diseases, such as cardiovascular diseases, cytotoxic T lymphocyte- or NK cell-derived GZMA nervous system diseases, and liver diseases. Hence, can cleave GSDMB to release its pore-forming many studies have focused on inhibiting pyroptosis to N-terminal domain for pyroptosis induction [50]. treat these diseases by targeting NLRP3, caspase-1, or Moreover, interferon-γ increased the expression of GSDMD. VX-765 is a safe and effective inhibitor of GSDMB to further promote pyroptosis (Figure 7B). caspase-1 that has been proved to be well tolerated in Heterologous overexpression of GZMA-cleavable phase II clinical trial in patients with partial epilepsy. human GSDMB in mouse cancer cells accelerates the Therefore, VX-765 is a clinical-grade drug that could elimination of tumors in vivo. This study identified a potentially be used in other pyroptosis-related novel killing mechanism of cytotoxic lymphocytes diseases. Another anti-pyroptotic drug currently in through gasdermin-mediated pyroptosis, which clinical application is lncRNA NBR2, which regulates ensures sufficient antitumor immunity. endothelial pyroptosis by targeting GSDMD in sepsis. Bioorthogonal chemistry presents a wonderful Nevertheless, due to non-specificity, many current strategy for investigating many biological processes, inhibitors may result in unexpected side effects. such as immunity and cell death in live animals. Further research is needed to improve the specificity Wang et al. constructed a nano-bioorthogonal of pyroptotic inhibitors. In addition, current chemical system, in which gasdermin A3 (GA3) was therapeutic targets for the treatment of these diseases linked to nanoparticles via the trimethylsilyl ether mainly focus on canonical inflammasome signaling, linker (NP-GA3), and this linker could be cleaved by a that is, the caspase-1/GSDMD pathway. It should be cancer-imaging probe phenylalanine trifluoroborate further investigated whether the non-canonical (Phe-BF3) [124]. When HeLa and EMT6 cells were inflammasome pathway or apoptotic caspases- treated with NP-GA3 and Phe-BF3, the cells showed mediated pathway of pyroptosis is implicated in these obvious pyroptotic morphology. It should be noted inflammatory diseases and can serve as therapeutic that only a small fraction of the tumor cells targets. undergoing pyroptosis could erase the entire tumor, Although pyroptosis produces pathogenic which implies the role of the immune system. effects on inflammatory diseases, as a pro-inflam- Furthermore, only one round of injection of NP-GA3 matory cell death, it also paves a new way for cancer and Phe-BF3 could not prevent tumor growth. In clearance by deliberate induction of pyroptotic cell contrast, tumor growth was markedly inhibited by death and intense antitumor immunity. In cancer, one round of injection plus anti-PD-1 therapy, which pyroptosis has been shown to be triggered by almost demonstrates that inflammation induced by all signaling pathways in which GSDME, GSDMD, pyroptosis can trigger robust antitumor immunity GSDMC, or GSDMB serve as the executors. Induction and synergize with immune checkpoint blockade for of pyroptosis to eliminate tumor cells has become a tumor immunotherapy. promising strategy for the treatment of tumor by boosting antitumor immunity. However, gasdermins Conclusion are also expressed in normal tissues. Extensive pyroptosis may cause severe damage to the normal Pyroptosis is a form of inflammatory PCD tissues. Hence, there are several points to be noted for mediated by gasdermin proteins, which are often pyroptosis-based cancer therapy. Firstly, how to activated by caspases. Initially, researchers focused on https://www.thno.org Theranostics 2022, Vol. 12, Issue 9 4325 specifically induce pyroptosis in cancer cells but not recurrence and metastasis; VTPA: virus-spike tumor- in normal cells for cancer therapy. Some studies have activatable pyroptotic agent; α-KG: α-ketoglutarate; designed TME responsive nanodrug to induce α-NETA: 2-(anaphthoyl) ethyl-trimethylammonium pyroptosis in cancer cells specifically. Secondly, how iodide. to visualize pyroptosis in vivo, to further improve its Acknowledgements accuracy. Future studies are urgently needed to develop more precise and tumor-specific pyroptotic This work was supported by the National Key treatments, and more clinical trials are needed to Research and Development Program of China (Nos. explore the potential application of pyroptosis-based 2017YFC1309100 and 2017YFA0205200), National cancer therapy. Natural Science Foundation of China (Nos. 21804104, 91959124, 81671753, 32101147 and 32071406), Abbreviations Innovation Capability Support Program of Shaanxi ASC: apoptosis-associated speck-like protein (Program No. 2022TD-52), Natural Science containing a caspase recruitment domain; AD: Foundation of Shaanxi Province of China alzheimer’s disease; AIM2: absent in melanoma 2; (No. 2020PT-020), The Youth Innovation Team of AMPCP: α, β-methylene adenosine 5’ diphosphate; Shaanxi Universities, Natural Science Basic Research AOZN: AMPCP and Orz loaded nanomicelles; ATP: Plan in Shaanxi Province of China (Nos. 2021JM-147 adenosine triphosphoric acid; Aβ: β-amyloid protein; and 2021JQ-212), and the Fundamental Research BNP: biomimetic nanoparticle; CARD: caspase Funds for the Central Universities (Nos. JB211201, recruitment domain-containing; CSCs: cancer stem JB211202, JB211204). cells; CXCR4: C-X-C motif chemokine receptor 4; Competing Interests DAC: decitabine; DC: dendritic cell; DITOX: diphtheria toxin; DR6: death receptor 6; FoxO1: The authors have declared that no competing forkhead box O1; GA3: gasdermin A3; GSDMD: interest exists. gasdermin D; GSDMD-NT: gasdermin D N-terminal References domain; GSH: glutathione; GZMA: granzyme A; GZMB: granzyme B; IBRN: implantable 1. Zychlinsky A, Prevost MC, Sansonetti PJ. Shigella flexneri induces apoptosis in infected macrophages. Nature. 1992; 358: 167-9. bio-responsive nanoarray; IL-18: interleukin-18; IL-1β: 2. Hilbi H, Chen Y, Thirumalai K, Zychlinsky A. 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Nanostructured toxins for the selective destruction of drug-resistant human CXCR4(+) colorectal cancer stem cells. J Control Release. 2020; 320: 96-104. 126. Zhou B, Zhang JY, Liu XS, Chen HZ, Ai YL, Cheng K, et al. Tom20 senses iron-activated ROS signaling to promote melanoma cell pyroptosis. Cell Res. 2018; 28: 1171-85. Author Biographies Dr. Pengbo Ning received his PhD from Northwest A&F University in 2013. He worked at the College of Veterinary Medicine, Northwest A&F University from 2007 to 2015, and the field of study was genome-wide analysis in interactions between viruses and macrophages. He then moved to the School of Life and Technology, Xidian University, as an Associate Professor, and his research focuses on gene-modified Dr. Zhiping Rao received macrophages and their potential application for her Ph.D. from the Institute of Neuroscience, State cancer immunotherapy and drug delivery. Key Laboratory of Neuroscience, CAS center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences in 2018. She then joined the School of Life and Technology, Xidian University as a lecturer and her research focuses on the programmed cell death and disease treatment, especially ferroptosis and pyroptosis-based cancer therapy. https://www.thno.org Theranostics 2022, Vol. 12, Issue 9 4329 Prof. Zhongliang Wang received his PhD from Institute of chemistry, Chinese Academy of Sciences in 2009. He then moved to the University of Florida as a postdoc fellow working with Professor Y. Charles Cao. In 2013, he joined the Laboratory of Molecular Imaging and Nanomedicine (LOMIN) at the National Institutes of Health (NIH) as a postdoctoral fellow under the supervision of Prof. Xiaoyuan (Shawn) Chen. In 2014, he joined the School of Life and Technology, Xidian University as a Professor and his research focuses on the development of smart and biomimetic materials for diagnostics and therapeutics of various diseases. https://www.thno.org

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Published: May 16, 2022

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