Gasdermin‐Mediated Pyroptosis: Novel Strategies Against Colorectal Cancer

Pyroptosis, a form of programmed cell death mediated by gasdermin proteins, has gained attention for its dual role in colorectal cancer (CRC) progression and therapy. While chronic pyroptosis-driven inflammation can promote tumorigenesis, acute induction of pyroptosis in tumor cells offers promising antitumor effects. Understanding the mechanisms and implications of pyroptosis in CRC could lead to novel therapeutic strategies. Gasdermin proteins, particularly GSDMD and GSDME, are central to pyroptotic processes in CRC. GSDMD activation, often through NLRP3 inflammasome signaling or chemotherapeutic agents like simvastatin, induces pyroptosis and modulates immune infiltration. Conversely, GSDMC has been implicated in CRC progression under metabolic stress by recruiting immunosuppressive cells. Although frequently silenced in CRC, GSDME enhances sensitivity to chemoradiation and synergizes with immune checkpoint inhibitors by releasing immunostimulatory molecules. Inflammasomes, notably NLRP3 and AIM2, also play significant roles in CRC pathogenesis through pyroptosis and cytokine secretion. NLRP3 activation exacerbates tumor growth via inflammatory pathways, while AIM2 exerts tumor-suppressive effects, especially in BRAF-mutant CRC. The gut microbiota further influences inflammasome activity, with certain strains promoting chemoresistance and others enhancing antitumor immunity. Therapeutically, inducing pyroptosis synergizes with conventional therapies and immunotherapies, overcoming apoptosis resistance and resensitizing tumors. Pyroptosis releases tumor antigens and damage-associated molecular patterns, recruiting cytotoxic lymphocytes and natural killer cells, thereby remodeling the immunosuppressive microenvironment. Pyroptosis represents a double-edged sword in CRC, offering both challenges and opportunities. Harnessing its antitumor potential while mitigating pro-tumorigenic inflammation requires innovative strategies. Future research should focus on elucidating the isoform-specific roles of gasdermins, optimizing therapeutic approaches to induce pyroptosis.