Penfluridol Triggers GSDME‐Mediated Immunogenic Pyroptosis to Potentiate Antitumor Immunotherapy

ABSTRACT The potential of pyroptosis in antitumor immunity is well‐established; however, its clinical translation is hindered by the lack of safe and effective pyroptosis inducers. Here, using a high‐throughput 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‐8/caspase‐3‐dependent cleavage of GSDME, culminating in pyroptotic cell death. Preclinically, PF not only exhibits monotherapy efficacy in immunocompetent hosts but also acts synergistically with anti‐PD‐1 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.