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

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.