PKCα regulates the secretion of PDL1-carrying small extracellular vesicles in a p53-dependent manner

作者：Ren Zhang, Weilin Liao, Xi Chen, Junyi Wang, Jiaqi Li, Geer Chen, Weiyu Wu, Xiaoxuan Wang, Yao Zhang, Ziyu Chen, Xiaoyu Zhu, Zicong Lin, Yi Zhun Zhu, Lijuan Ma, Haijie Yu · 发表于：Cell Death and Disease · 年份：2025 · DOI：10.1038/s41419-025-07341-5 · 被引用次数：6 · 研究领域：Extracellular vesicles in disease、Phagocytosis and Immune Regulation、MicroRNA in disease regulation

Small extracellular vesicles (sEVs), carrying PD-L1, have been implicated in immune evasion and tumor progression. However, understanding how PD-L1 sEVs are secreted still needs to be improved. We found that the secretion dynamics of PD-L1 sEVs is similar to that of other sEVs. Intracellular calcium and the associated downstream PKC signaling plays pivotal roles in releasing PD-L1 sEVs in non-small cell lung cancer cells (NSCLC). Particularly, we observed that knocking down PKCα has profound impacts on PD-L1 sEVs secretion, especially in the resting state and in the activated state, when induced by an intracellular calcium rise. Furthermore, our study revealed that PKCα regulates PD-L1 expression and PD-L1 sEVs secretion by influencing STAT1 phosphorylation and nuclear translocation in a p53-dependent manner. Notably, p53 can regulate STAT1 phosphorylation and nuclear localization, but it does not affect PKCα expression. This suggests that PKCα plays a significant role in regulating PD-L1 expression. Our findings suggest that targeting PKCα to modulate PD-L1 dynamics in NSCLC may be a promising therapeutic strategy to enhance the efficacy of immunotherapeutic interventions.