VCP downstream metabolite glycerol-3-phosphate (G3P) inhibits CD8+T cells function in the HCC microenvironment

作者：Cheng Cheng, Qingrui Zha, Linmao Sun, Tianming Cui, Xinyu Guo, Changjian Xing, Zhengxiang Chen, Changyong Ji, Shuhang Liang, Shengwei Tao, Junhui Chu, Chenghui Wu, Qi Chu, Xuetian Gu, Ning Zhang, Yumin Fu, Shumin Deng, Yitong Zhu, Jiabei Wang, Yao Liu, Lianxin Liu · 发表于：Signal Transduction and Targeted Therapy · 年份：2025 · DOI：10.1038/s41392-024-02120-8 · 被引用次数：11 · 研究领域：Immune Cell Function and Interaction、Cancer Immunotherapy and Biomarkers、Immune cells in cancer

Abstract CD8 + T cells within the tumor microenvironment (TME) are often functionally impaired, which limits their ability to mount effective anti-tumor responses. However, the molecular mechanisms behind this dysfunction remain incompletely understood. Here, we identified valosin-containing protein (VCP) as a key regulator of CD8 + T cells suppression in hepatocellular carcinoma (HCC). Our findings reveal that VCP suppresses the activation, expansion, and cytotoxic capacity of CD8 + T cells both in vitro and in vivo, significantly contributing to the immunosuppressive nature of the TME. Mechanistically, VCP stabilizes the expression of glycerol-3-phosphate dehydrogenase 1-like protein (GPD1L), leading to the accumulation of glycerol-3-phosphate (G3P), a downstream metabolite of GPD1L. The accumulated G3P diffuses into the TME and directly interacts with SRC-family tyrosine kinase LCK, a critical component of the T-cell receptor (TCR) signaling pathway in CD8 + T cells. This interaction heightens the phosphorylation of Tyr505, a key inhibitory residue, ultimately reducing LCK activity and impairing downstream TCR signaling. Consequently, CD8 + T cells lose their functional capacity, diminishing their ability to fight against HCC. Importantly, we demonstrated that targeting VCP in combination with anti-PD1 therapy significantly suppresses HCC tumor growth and restores the anti-tumor function of CD8 + T cells, suggesting synergistic therapeutic potential. These findings highlig...