Gasdermin E (GSDME) is a pore-forming protein that can induce inflammatory cell death (pyroptosis) when cleaved by caspase 3. GSDME expression is suppressed in many cancers, and reduced GSDME levels are associated with decreased survival in breast cancer. The study shows that 20 out of 22 tested cancer-associated GSDME mutations reduce GSDME function. In mice, knocking out Gsdme in GSDME-expressing tumours enhances tumour growth, while ectopic expression of GSDME in Gsdme-repressed tumours inhibits tumour growth. This tumour suppression is mediated by killer cytotoxic lymphocytes, as it is abrogated in perforin-deficient mice or mice depleted of killer lymphocytes. GSDME expression enhances the phagocytosis of tumour cells by tumour-associated macrophages and the number and functions of tumour-infiltrating natural-killer and CD8+ T lymphocytes. Killer-cell granzyme B also activates caspase-independent pyroptosis in target cells by directly cleaving GSDME at the same site as caspase 3. Uncleavable or pore-defective GSDME proteins are not tumour suppressive. Thus, GSDME acts as a tumour suppressor by activating pyroptosis and enhancing anti-tumour immunity.Gasdermin E (GSDME) is a pore-forming protein that can induce inflammatory cell death (pyroptosis) when cleaved by caspase 3. GSDME expression is suppressed in many cancers, and reduced GSDME levels are associated with decreased survival in breast cancer. The study shows that 20 out of 22 tested cancer-associated GSDME mutations reduce GSDME function. In mice, knocking out Gsdme in GSDME-expressing tumours enhances tumour growth, while ectopic expression of GSDME in Gsdme-repressed tumours inhibits tumour growth. This tumour suppression is mediated by killer cytotoxic lymphocytes, as it is abrogated in perforin-deficient mice or mice depleted of killer lymphocytes. GSDME expression enhances the phagocytosis of tumour cells by tumour-associated macrophages and the number and functions of tumour-infiltrating natural-killer and CD8+ T lymphocytes. Killer-cell granzyme B also activates caspase-independent pyroptosis in target cells by directly cleaving GSDME at the same site as caspase 3. Uncleavable or pore-defective GSDME proteins are not tumour suppressive. Thus, GSDME acts as a tumour suppressor by activating pyroptosis and enhancing anti-tumour immunity.