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Cepharanthine Triggers Immunogenic Cell Death in Solid Tumors by Suppressing PKCζ/NF-κB-Driven PARP1 Expression and Synergizes with Immunotherapy

ABSTRACT: Induction of immunogenic cell death (ICD) represents a promising strategy to suppress tumor growth and enhance antitumor immunity, highlighting the urgent need to develop more safe and effective ICD inducers. Through screening of a panel of natural alkaloids, we identified cepharanthine (CEP) as a potent ICD inducer in solid tumors. CEP treatment promotes damage-associated molecular pattern (DAMP) release, enhances antigen-presenting cell phagocytosis, and subsequently activates T cell-mediated immunity. CEP-induced ICD is featured by intracellular reactive oxygen species (ROS) accumulation, DNA damage, and endoplasmic reticulum (ER) stress. Mechanistically, CEP directly binds to protein kinase C zeta (PKCζ), and inhibits the NF-κB signaling pathway, leading to attenuated nuclear translocation of p65 and subsequent poly ADP-ribose polymerase 1 (PARP1) transcription. The ICD-inducing effect of CEP depends on PARP1 downregulation. Furthermore, CEP significantly enhances the therapeutic efficacy of PD-1 antibody and OX40 agonist antibody in syngeneic mouse tumor models. Hematological and biochemical analyses confirm the favorable biosafety profile of CEP. These findings demonstrate the clinical translatable potential of CEP as a novel ICD inducer for cancer immunotherapy.

ORGANISM(S): Mus musculus

PROVIDER: GSE300262 | GEO | 2026/05/01

REPOSITORIES: GEO

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