Colorectal cancer remains one of the leading causes of cancer mortality worldwide, and resistance to conventional chemotherapy and immunotherapy continues to frustrate clinical outcomes. A growing body of mechanistic research now points to a form of inflammatory cell death — pyroptosis — as a targetable vulnerability in tumor biology, with implications for how oncologists might redesign combination therapy strategies.

This review, published in Cancer Science, maps the complex landscape of gasdermin-protein-mediated pyroptosis in colorectal cancer (CRC). Four gasdermin family members take center stage: GSDMD and GSDME are identified as tumor-suppressive effectors, while GSDMC paradoxically promotes tumor progression under metabolic stress conditions by recruiting immunosuppressive cells into the tumor microenvironment. GSDMD is activated via the NLRP3 inflammasome pathway and by chemotherapeutic agents including simvastatin, triggering pyroptotic cell death and reshaping immune infiltration patterns. GSDME, frequently silenced through epigenetic mechanisms in CRC, when re-expressed enhances tumor sensitivity to chemoradiation and synergizes with immune checkpoint inhibitor therapy by liberating immunostimulatory danger signals. At the inflammasome level, NLRP3 activation drives pro-tumorigenic inflammatory cascades, whereas AIM2 exerts suppressive effects — particularly in BRAF-mutant CRC subtypes. The gut microbiome emerges as an additional regulatory layer, with specific bacterial strains modulating inflammasome tone toward either chemoresistance or antitumor immunity.

This review synthesizes a rapidly evolving mechanistic field, but important caveats apply. Much of the evidence derives from preclinical cell-line and murine models; clinical validation in human CRC cohorts remains sparse. The context-dependent nature of pyroptosis — chronically promoting tumorigenesis yet acutely killing tumor cells — means that therapeutic induction will require precise timing and tumor-compartment selectivity to avoid worsening systemic inflammation. Nonetheless, the convergence of gasdermin biology, inflammasome pharmacology, microbiome modulation, and checkpoint immunotherapy represents a genuinely multi-pronged therapeutic hypothesis. For researchers and clinicians following immuno-oncology, this synthesis is more confirmatory than paradigm-shifting, but it usefully consolidates the mechanistic rationale for pyroptosis-inducing strategies as adjuncts to existing CRC treatment regimens.