Gasdermin E (GSDME) suppresses tumour growth by activating anti-tumour immunity. GSDME, a gasdermin protein, is cleaved by caspase 3 to induce pyroptosis, a form of inflammatory cell death. GSDME expression is suppressed in many cancers, and reduced levels are associated with decreased survival in breast cancer, suggesting GSDME acts as a tumour suppressor. 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, whereas ectopic expression in Gsdme-repressed tumours inhibits, tumour growth. This tumour suppression is mediated by killer cytotoxic lymphocytes, which are abrogated in perforin-deficient mice or mice depleted of killer lymphocytes. GSDME expression enhances the phagocytosis of tumour cells by tumour-associated macrophages, as well as 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, tumour GSDME acts as a tumour suppressor by activating pyroptosis, enhancing anti-tumour immunity. The study provides evidence that GSDME might act as a tumour suppressor, including epigenetic GSDME inactivation by promoter DNA methylation in many cancer lines and primary cancers, suppression by GSDME of colony formation and cell proliferation in gastric cancer, melanoma and colorectal cancer and of breast-cancer invasiveness, and worse five-year survival and increased metastases from breast cancers that poorly express GSDME. The study shows that GSDME in tumours suppresses tumour growth by increasing the anti-tumour functions of tumour-infiltrating natural-killer (NK) and CD8+ T killer lymphocytes. GSDME converts apoptosis to pyroptosis by cleavage by caspase 3. Loss-of-function GSDME mutations in cancer were examined, and it was found that 20 of 22 studied cancer-related GSDME mutations cause LOF. GSDME affects tumour growth and immunity by inducing pyroptosis, which enhances anti-tumour immunity. Killer lymphocytes mediate tumour suppression by cleaving GSDME and inducing GSDME-dependent pyroptosis in target cells. Granzyme B cleaves GSDME after D270, which is essential for tumour suppression. D270 cleavage mediates tumour suppression by activating GSDME and inducing pyroGasdermin E (GSDME) suppresses tumour growth by activating anti-tumour immunity. GSDME, a gasdermin protein, is cleaved by caspase 3 to induce pyroptosis, a form of inflammatory cell death. GSDME expression is suppressed in many cancers, and reduced levels are associated with decreased survival in breast cancer, suggesting GSDME acts as a tumour suppressor. 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, whereas ectopic expression in Gsdme-repressed tumours inhibits, tumour growth. This tumour suppression is mediated by killer cytotoxic lymphocytes, which are abrogated in perforin-deficient mice or mice depleted of killer lymphocytes. GSDME expression enhances the phagocytosis of tumour cells by tumour-associated macrophages, as well as 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, tumour GSDME acts as a tumour suppressor by activating pyroptosis, enhancing anti-tumour immunity. The study provides evidence that GSDME might act as a tumour suppressor, including epigenetic GSDME inactivation by promoter DNA methylation in many cancer lines and primary cancers, suppression by GSDME of colony formation and cell proliferation in gastric cancer, melanoma and colorectal cancer and of breast-cancer invasiveness, and worse five-year survival and increased metastases from breast cancers that poorly express GSDME. The study shows that GSDME in tumours suppresses tumour growth by increasing the anti-tumour functions of tumour-infiltrating natural-killer (NK) and CD8+ T killer lymphocytes. GSDME converts apoptosis to pyroptosis by cleavage by caspase 3. Loss-of-function GSDME mutations in cancer were examined, and it was found that 20 of 22 studied cancer-related GSDME mutations cause LOF. GSDME affects tumour growth and immunity by inducing pyroptosis, which enhances anti-tumour immunity. Killer lymphocytes mediate tumour suppression by cleaving GSDME and inducing GSDME-dependent pyroptosis in target cells. Granzyme B cleaves GSDME after D270, which is essential for tumour suppression. D270 cleavage mediates tumour suppression by activating GSDME and inducing pyro