Scholarlink

<p>CD8<sup>+</sup>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<sup>+</sup>T cells suppression in hepatocellular carcinoma (HCC). Our findings reveal that VCP suppresses the activation, expansion, and cytotoxic capacity of CD8<sup>+</sup>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<sup>+</sup>T cells. This interaction heightens the phosphorylation of Tyr505, a key inhibitory residue, ultimately reducing LCK activity and impairing downstream TCR signaling. Consequently, CD8<sup>+</sup>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<sup>+</sup>T cells, suggesting synergistic therapeutic potential. These findings highlight a previously unrecognized mechanism involving VCP and G3P in suppressing T-cell-mediated immunity in the TME, positioning VCP as a promising upstream target for enhancing immunotherapy in HCC.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

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

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年1月24日

查看全文
  • 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

摘要

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 highlight a previously unrecognized mechanism involving VCP and G3P in suppressing T-cell-mediated immunity in the TME, positioning VCP as a promising upstream target for enhancing immunotherapy in HCC.