Cholangiocarcinoma PDHA1 succinylation suppresses macrophage antigen presentation via alpha-ketoglutaric acid accumulation
Ning Zhang, Linmao Sun, Shuo Zhou, Changyong Ji, Tianming Cui, Qi Chu, Jingyang Ye, Shuhang Liang, Kun Ma, Yufeng Liu, Xianying Li, Xinyu Guo, Wei Zhang, Xuetian Gu, Cheng Cheng, Qingrui Zha, Shengwei Tao, Yunguang Zhang, Junhui Chu, Chenghui Wu, Yuchen Zhang, Jiabei Wang, Yao Liu, Lianxin Liu, Yao Liu, Lianxin Liu
Abstract
Gemcitabine combined with cisplatin is the first-line chemotherapy for advanced cholangiocarcinoma, but drug resistance remains a challenge, leading to unsatisfactory therapeutic effect. Here, we elucidate the possibility of chemotherapy regimens sensitized by inhibiting succinylation in patients with cholangiocarcinoma from the perspective of post-translational modification. Our omics analysis reveals that succinylation of PDHA1 lysine 83, a key enzyme in the tricarboxylic acid cycle, alters PDH enzyme activity, modulates metabolic flux, and leads to alpha-ketoglutaric acid accumulation in the tumor microenvironment. This process activates the OXGR1 receptor on macrophages, triggering MAPK signaling and inhibiting MHC-II antigen presentation, which promotes immune escape and tumor progression. Moreover, we show that inhibiting PDHA1 succinylation with CPI-613 enhances the efficacy of gemcitabine and cisplatin. Targeting PDHA1 succinylation may be a promising strategy to improve treatment outcomes in cholangiocarcinoma and warrants further clinical exploration. Succinylation, a posttranslational modification on lysine residues, is involved in tumor progression. Here, authors show that PDHA1 K83 succinylation is involved in cholangiocarcinoma tumorigenesis through regulation of macrophage antigen presentation in the tumor microenvironment