Hearing loss-associated protein gasdermin E (GSDME), an effector of secondary necrosis, has been identified in a new pathway of programmed cell death (PCD). GSDME epigenetic silencing and mutations resulting in loss-of-function have been reported in cancer tissues. Additionally, GSDME upregulation inhibits tumor proliferation as well as colony forming ability, and reduces the incidence of lymphatic metastasis, demonstrating that GSDME may act as a tumor suppressor. Here, we have focused on the molecular mechanisms of GSDME-mediated PCD, and tried to reveal the crosstalk between this cell death pathway and apoptosis, autophagy, GSDMD-mediated pyroptosis. Moreover, we concluded the anti-cancer activity of GSDME include forming permeable membranes, and triggering anti-cancer immunity. Thus, GSDME was potential to be a novel target for cancer prevention and treatment.