Gasdermin‐Mediated Pyroptosis: Novel Strategies Against Colorectal Cancer

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  FIGURE 1. Graphical abstract.

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  FIGURE 2. Schematic representation of canonical and noncanonical inflammasome pathways in pyroptosis. The canonical inflammasome pathway is initiated by sensor proteins (e.g., NLRP3, NLRP1b, NLRC4, AIM2, and pyrin) that detect pathogen‐ or damage‐associated molecular patterns through ligand‐specific interactions. For example, NLRP3 responds to diverse stimuli such as bacterial pore‐forming toxins, fungal peptides, viral dsRNA, and DAMPs (Alu RNA, ox‐mtDNA, S100A8/S100A9, Prdx1, ATP), while NLRP1b is triggered by anthrax lethal toxin, NLRC4 by bacterial flagellin or type III secretion system components, AIM2 by cytosolic bacterial/viral dsDNA, and pyrin by Rho GTPase inactivation mediated by bacterial toxins. Upon activation, these sensors oligomerize and recruit the adaptor protein ASC, which facilitates pro‐caspase‐1 recruitment and its autocatalytic cleavage into active caspase‐1. This effector protease then processes pro‐IL‐1β and pro‐IL‐18 into mature cytokines and cleaves gasdermin D (GSDMD), releasing its N‐terminal pore‐forming fragment. GSDMD‐mediated plasma membrane permeabilization enables secretion of IL‐1β, IL‐18, and HMGB1. In contrast, the noncanonical pathway bypasses ASC…

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  FIGURE 3. Caspase3/8 and granzyme‐mediated pyroptotic pathways. The virulence factor YopJ from Yersinia pestis triggers caspase‐8‐dependent pyroptosis by inhibiting TAK1, a regulatory kinase required for survival signaling. TAK1 suppression induces caspase‐8 activation, which directly cleaves gasdermin D (GSDMD) to generate pore‐forming N‐terminal fragments, driving membrane permeabilization and inflammatory cell death. Separately, caspase‐3 activated by chemotherapeutic agents cleaves gasdermin E (GSDME) to produce its cytotoxic N‐terminal domain, bypassing canonical inflammasome pathways to initiate pyroptosis. In parallel, cytotoxic lymphocytes (e.g., T cells, NK cells) induce caspase‐independent pyroptosis in tumor cells through granzyme‐mediated cleavage of gasdermins: Granzyme A specifically processes GSDMB, while granzyme B targets GSDME, both generating membrane‐disruptive fragments that execute pyroptosis independent of caspase signaling.

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  FIGURE 4. Therapeutic regimen‐induced CRC cells pyroptosis potentiates antitumor immunity. Multiple cancer therapies, including radiotherapy, chemotherapy, targeted therapy, and natural products, induce pyroptosis in CRC cells. Pyroptotic tumor cells release immunostimulatory damage‐associated molecular patterns (DAMPs), tumor‐associated antigens (TAAs), and proinflammatory cytokines, collectively enhancing the recruitment, phagocytic capacity, and maturation of antigen‐presenting cells (APCs). APCs process TAAs and present them via major histocompatibility complex class II (MHC II) to activate naïve CD8+ T cells, driving their differentiation into tumor antigen‐specific cytotoxic T lymphocytes (CTLs). Concurrently, pyroptosis‐generated inflammatory signals within the tumor microenvironment recruit CTLs and natural killer (NK) cells. These effector cells eliminate gasdermin‐expressing tumor cells through granzyme A/B (GzmA/B)‐mediated cleavage of gasdermins, thereby perpetuating pyroptosis‐driven immunostimulation and establishing a feed‐forward loop for sustained antitumor responses.

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  FIGURE 5. Immunomodulatory dynamics and chronic inflammation in the CRC tumor microenvironment. The activation of NLRP3 inflammasome in intestinal epithelial cells by damage‐associated molecular patterns (DAMPs) and pathogen‐associated molecular patterns (PAMPs) drives chronic intestinal inflammation. This persistent inflammatory state induces gut microbiota dysbiosis, characterized by diminished abundance of beneficial commensals including Akkermansia muciniphila and Lactobacillus plantarum OC01, alongside pathogenic Escherichia coli overrepresentation. These alterations collectively establish a tumor‐permissive immune microenvironment through sustained cytokine dysregulation and epithelial barrier compromise, ultimately progressing to colorectal carcinogenesis through cumulative genomic instability. The CRC immune landscape comprises stromal cells, malignant epithelial cells, T cells, natural killer (NK) cells, and macrophages. Pyroptotic immune cells induced by NLRP3 inflammasome, particularly macrophages, release interleukin (IL)‐18 and IL‐1β, which exert opposing roles in tumor progression. IL‐18 suppresses CRC growth by enhancing macrophage activity, boosting CD8+ T cell and NK cell…

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  FIGURE 6. The immunological consequences of pyroptosis exhibit biphasic characteristics dependent on activation intensity. During this lytic cell death process, pyroptotic cells discharge bioactive molecules including pro‐inflammatory cytokines (IL‐1β, IL‐18) and damage‐associated molecular patterns (DAMPs) that serve as alarmins to modulate immune surveillance. Chronic low‐grade pyroptosis in malignant cells establishes a tumor‐promotive niche through sustained subclinical inflammation and microenvironmental conditioning that facilitates neoplastic proliferation and metastatic dissemination. Conversely, therapeutic induction of extensive pyroptotic cascades initiates profound immunostimulatory effects. The liberation of intracellular contents in this context drives robust leukocyte infiltration and activates coordinated antitumor immunity through antigen‐presenting cell maturation and cytotoxic lymphocyte priming, ultimately culminating in tumor regression through immunogenic clearance mechanisms.