Scholarlink

<p>T cell senescence significantly impairs the efficacy of immune checkpoint blockade (ICB) therapy in cancer. Metabolic reprogramming is a crucial factor in T cell senescence in tumor microenvironment (TME). Ovarian cancer (OvCa) patients derive limited benefit from ICB treatment, probably related to T cell senescence. OvCa cells metastasize to the abdominal cavity rich in omental fat and raise ascites, forming a unique TME, adipocyte-rich TME. In this study, we investigated the effects of adipocyte-rich TME on T cell senescence. Using the single-cell RNA sequencing of OvCa and clinical samples, we found that adipocyte-rich TME is strongly associated with the formation of senescence CD8<sup>+</sup>T (CD8<sup>+</sup>Tsen) cells. Mechanistically, adipocyte-derived factors (MATES) and oleic acid (OA)-the predominant fatty acid in OvCa ascites-promoted tumor-induced CD8<sup>+</sup>Tsen formation by enhancing fatty acid (FA) uptake via FABP4, triggering lipid peroxidation rather than energy production. Inhibition of <i>FABP4</i> (using the inhibitor BMS309403 or siRNA knockdown) blocked CD8<sup>+</sup>Tsen cell formation, reduced lipid peroxidation, restored CD8<sup>+</sup>T cell effector function, and suppressed immunosuppressive cytokines. Moreover, using an OvCa mouse model, we found that in OvCa mice BMS309403 treatment partially diminished CD8<sup>+</sup>Tsen formation by reducing FA uptake, and improved anti-tumor immunity, and prolonged the survival time of OvCa mice when combined with chemotherapy. Our work suggests <i>FABP4</i>-mediated FA metabolism as a therapeutic target to counteract T cell senescence in adipocyte-rich TME, providing a novel immunotherapeutic strategy for OvCa.</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

Fatty acid uptake mediated by FABP4 promotes the formation of CD8+T cell senescence through lipid peroxidation in the adipocyte-rich microenvironment of Ovarian Cancer

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年2月6日

查看全文
  • Chunyan Yu,
  • Xin Li,
  • Xiaolong Qian,
  • Haoke Zhang,
  • Xueying Li,
  • Bo Wang,
  • Mantong Li,
  • Zixuan Liu,
  • Wei Du,
  • Siqi Chen,
  • Yuqing Ouyang,
  • Xiaofan Feng,
  • Tianhui He,
  • Zihe Liu,
  • Haixia Wu,
  • Xiaoyan Zheng,
  • Junru Liu,
  • Hong Zhang,
  • Yuanming Song,
  • Chenying Liu,
  • Jiazhen Li,
  • Hongyan Guo,
  • Shiwen Xu,
  • Xiaojing Guo,
  • Weimin Deng

摘要

T cell senescence significantly impairs the efficacy of immune checkpoint blockade (ICB) therapy in cancer. Metabolic reprogramming is a crucial factor in T cell senescence in tumor microenvironment (TME). Ovarian cancer (OvCa) patients derive limited benefit from ICB treatment, probably related to T cell senescence. OvCa cells metastasize to the abdominal cavity rich in omental fat and raise ascites, forming a unique TME, adipocyte-rich TME. In this study, we investigated the effects of adipocyte-rich TME on T cell senescence. Using the single-cell RNA sequencing of OvCa and clinical samples, we found that adipocyte-rich TME is strongly associated with the formation of senescence CD8+T (CD8+Tsen) cells. Mechanistically, adipocyte-derived factors (MATES) and oleic acid (OA)-the predominant fatty acid in OvCa ascites-promoted tumor-induced CD8+Tsen formation by enhancing fatty acid (FA) uptake via FABP4, triggering lipid peroxidation rather than energy production. Inhibition of FABP4 (using the inhibitor BMS309403 or siRNA knockdown) blocked CD8+Tsen cell formation, reduced lipid peroxidation, restored CD8+T cell effector function, and suppressed immunosuppressive cytokines. Moreover, using an OvCa mouse model, we found that in OvCa mice BMS309403 treatment partially diminished CD8+Tsen formation by reducing FA uptake, and improved anti-tumor immunity, and prolonged the survival time of OvCa mice when combined with chemotherapy. Our work suggests FABP4-mediated FA metabolism as a therapeutic target to counteract T cell senescence in adipocyte-rich TME, providing a novel immunotherapeutic strategy for OvCa.