Igniting Antitumour Immunity with Cancer Cell Pyroptosis

Gasdermins (GSDMs) are a family of pore-forming proteins that execute pyroptosis, a lytic form of programmed cell death associated with membrane rupture. This function of GSDMs was initially identified from studies of gasdermin D (GSDMD), which is cleaved and activated by inflammatory caspases in the inflammasome pathway. It is now established that other eukaryotic or pathogen-encoded proteases, as well as post-translational modifications, can also activate GSDM family members independent of inflammasomes and in multiple cell types including cancer cells. T cell granzyme-mediated GSDM activation, exogenous delivery of active GSDMs, and small molecule-induced activation of GSDMs in cancer cells have been shown to promote antitumour immunity through pyroptosis. Notably, only a fraction of cancer cells needs to undergo pyroptosis to induce immune cell infiltration and antitumour immunity with tolerable toxicity. Here, we summarize current knowledge on the role of pyroptosis in antitumour immunity, discuss pyroptosis in the context of other lytic forms of cell death, and provide an outlook on how cancer cell pyroptosis may synergize with existing immunotherapies.