Gasdermin E suppresses tumor growth by activating anti-tumor immunity

Cleavage of the gasdermins to produce a pore-forming N-terminal fragment causes inflammatory death (pyroptosis)(1). Caspase-3 cleaves gasdermin E (GSDME, also known as DFNA5), mutated in familial aging-related hearing loss(2), which converts noninflammatory apoptosis to pyroptosis in GSDME-expressing cells(3–5). GSDME expression is suppressed in many cancers and reduced GSDME is associated with decreased breast cancer survival(2,6), suggesting GSDME might be a tumor suppressor. Here we show reduced GSDME function of 20 of 22 tested cancer-associated mutations. Gsdme knockout in GSDME-expressing tumors enhances, while ectopic expression in Gsdme-repressed tumors inhibits, tumor growth. Tumor suppression is mediated by cytotoxic lymphocyte killing since it is abrogated in perforin-deficient or killer lymphocyte-depleted mice. GSDME expression enhances tumor-associated macrophage phagocytosis and the number and functions of tumor-infiltrating NK 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. Non-cleavable or pore-defective GSDME are not tumor suppressive. Thus, tumor GSDME is a tumor suppressor by activating pyroptosis, which enhances anti-tumor immunity.