Related Experiment Video
Updated: Jul 4, 2026
Examination of Pyroptosis by Flow Cytometry
Published on: May 31, 2024
Penfluridol Triggers GSDME-Mediated Immunogenic Pyroptosis to Potentiate Antitumor Immunotherapy
Linfeng Li1,2, Daishi Li1,3,4,5,6,7, Danyao Chen2
1Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan, China.
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.
Insights
Researchers identified penfluridol, an FDA-approved antipsychotic, as a potent pyroptosis inducer. This discovery offers a new strategy for stimulating antitumor immunity and improving cancer immunotherapy response.
Area of Science:
- Immunology
- Oncology
- Pharmacology
Background:
- Pyroptosis is crucial for antitumor immunity, but clinical use is limited by a lack of safe and effective inducers.
- Developing novel pyroptosis-inducing agents is essential for advancing cancer immunotherapy.
Purpose of the Study:
- To identify safe and effective pyroptosis inducers for clinical translation.
- To explore the potential of repurposed drugs for cancer immunotherapy.
Main Methods:
- High-throughput screening of 240 FDA-approved antipsychotic agents.
- Investigated the molecular pathway of penfluridol-induced pyroptosis.
- Evaluated penfluridol's efficacy in preclinical cancer models (melanoma, HCC) and in combination with anti-PD-1 therapy.
- Correlated TTI1 expression and TNFA signaling with clinical immunotherapy response.
Main Results:
- Penfluridol (PF) was identified as a potent pyroptosis inducer through a novel pathway involving TTI1 inhibition, TNFA/NFKB activation, and GSDME cleavage.
- PF demonstrated monotherapy efficacy and synergistic effects with anti-PD-1 therapy in immunocompetent hosts without systemic toxicity.
- Low TTI1 expression and activated TNFA/NFKB signaling correlated with better immunotherapy response and survival.
Conclusions:
- Penfluridol is a promising repurposed drug for inducing pyroptosis and enhancing antitumor immunity.
- The TTI1/TNFA/NFKB pathway serves as a potential predictive biomarker for immunotherapy response.
- This study provides a new paradigm for developing pyroptosis inducers for cancer treatment.
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