GSDME-Mediated Pyroptosis Suppresses Anti-Tumor Immunity via IL-1α—Dependent Recruitment of Immunosuppressive Myeloid Cells 2309550

Abstract Introduction Pyroptosis is widely recognized as an immunogenic form of cell death that promotes anti-tumor immunity. Gasdermin E (GSDME), cleaved by caspase-3 in tumor cells, has therefore been proposed as a tumor suppressor. Here, we report an unexpected immunosuppressive role of GSDME-mediated pyroptosis in cancer development. Methods A genetically engineered spontaneous C-Myc+ Tp53⁻/⁻ murine HCC model was used. Hepatocyte-specific deletion of Gsdme and/or Il1a was achieved using conditional knockout strategies. Tumor growth was assessed in immune-competent and immune-deficient mice. Tumor-infiltrating immune cells were analyzed by flow cytometry. Cytokine release mechanisms were studied in hepatocytes and tumor cells. Human HCC samples were analyzed by immunohistochemistry to assess GSDME expression and its association with tumor stage. Results Hepatocyte-specific deletion of Gsdme significantly delayed tumor growth in immune-competent mice but not in immune-deficient hosts, indicating an immune-dependent mechanism. Although GSDME directly promoted tumor cell death in vitro, its expression in vivo was associated with impaired anti-tumor immunity, characterized by reduced infiltration of cytotoxic T and NK cells and increased accumulation of CD11b+ immunosuppressive myeloid cells. Mechanistically, GSDME pores facilitated interleukin-1α (IL-1α) secretion from tumor cells independently of overt plasma membrane rupture and were associated with calpain activation and nuclear membrane permeabilization. Il1a deletion phenocopied Gsdme deficiency, and combined deletion of Gsdme and Il1a did not confer additional tumor protection. In human HCC, high GSDME expression correlated with advanced tumor stage. Conclusion These findings uncover a previously unrecognized immunosuppressive function of GSDME-mediated pyroptosis in cancer. By promoting IL-1α—driven recruitment of suppressive myeloid cells, GSDME can impair anti-tumor immunity, challenging the paradigm that pyroptosis is uniformly beneficial in cancer. Funding Source n/a. Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)