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Here, using a high\u2010throughput screen of 240 antipsychotic agents approved by the Food and Drug Administration (FDA), we identify the antipsychotic agent penfluridol (PF) as a potent inducer of pyroptosis via a previously unreported molecular pathway. Mechanistically, PF directly binds to and inhibits TTI1, leading to activation of the TNFA signaling via NFKB and subsequent caspase\u20108\/caspase\u20103\u2010dependent cleavage of GSDME, culminating in pyroptotic cell death. Preclinically, PF not only exhibits monotherapy efficacy in immunocompetent hosts but also acts synergistically with anti\u2010PD\u20101 therapy in both transplanted and spontaneous melanoma and HCC models without inducing systemic toxicity. Clinically, low TTI1 expression coupled with activated TNFA signaling via NFKB correlates with improved immunotherapy response and prolonged overall survival, suggesting its potential utility as a predictive biomarker. Collectively, our work establishes a compelling paradigm for repurposing pyroptosis inducers to stimulate antitumor immunity.<\/jats:p>","DOI":"10.1002\/advs.76408","type":"journal-article","created":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T11:41:04Z","timestamp":1783078864000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Penfluridol Triggers GSDME\u2010Mediated Immunogenic Pyroptosis to Potentiate Antitumor Immunotherapy"],"prefix":"10.1002","volume":"13","author":[{"given":"Linfeng","family":"Li","sequence":"first","affiliation":[{"name":"Department of Dermatology Xiangya Hospital Central South University  Changsha Hunan China"},{"name":"Department of Thoracic Surgery Xiangya Hospital Central South University  Changsha Hunan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daishi","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Dermatology Xiangya 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