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<p>Glycolysis and mitochondrial fatty acid oxidation (FAO) regulate CD8<sup>+</sup> T cell differentiation, but how this metabolic balance regulates T cell exhaustion is unclear. PD-1 signaling inhibits glycolysis and enhances FAO. Here, we show that CD8<sup>+</sup> T cells in tumors adhere to glycolysis with attenuated FAO despite high PD-1 expression. Active aldehydes, final products of lipid peroxidation, accumulate in CD8<sup>+</sup> T cells in proportion to their level of exhaustion, defined by mitochondrial mass and potential. Aldehydes promote glycolysis and inhibit FAO in T cells. Mice deficient in an FAO enzyme in T cells generate more acrolein, a representative aldehyde, enhancing T cell exhaustion and attenuating antitumor immunity. Acrolein is generated partly from mitochondria and damages mitochondrial architecture. Inhibitors of lipid peroxidation or aldehydes enhanced PD-1-blockade by rectifying metabolic imbalance. Therefore, active aldehydes resulting from FAO impairment can cause a vicious cycle of metabolic imbalance that leads to T cell exhaustion.</p>

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Active aldehydes accelerate CD8+ T cell exhaustion by metabolic alteration in the tumor microenvironment

  • 期刊论文

  • 发表日期：

    2026年1月7日

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  • Yasuharu Haku,
  • Koji Kitaoka,
  • Koki Ichimaru,
  • Tomoko Hirano,
  • Jun Wang,
  • Kazuhiro Sonomura,
  • Asuka Maruo,
  • Shuhei Hirose,
  • Yu Wang,
  • Katsuhiro Ito,
  • Tomohiro Kozuki,
  • Keiko Yurimoto,
  • Mai Kiyono,
  • Hidetaka Kosako,
  • Toshi Menju,
  • Hiroshi Date,
  • Takashi Kobayashi,
  • Koichi Omori,
  • Tomonori Yaguchi,
  • Tasuku Honjo,
  • Kenji Chamoto

摘要

Glycolysis and mitochondrial fatty acid oxidation (FAO) regulate CD8+ T cell differentiation, but how this metabolic balance regulates T cell exhaustion is unclear. PD-1 signaling inhibits glycolysis and enhances FAO. Here, we show that CD8+ T cells in tumors adhere to glycolysis with attenuated FAO despite high PD-1 expression. Active aldehydes, final products of lipid peroxidation, accumulate in CD8+ T cells in proportion to their level of exhaustion, defined by mitochondrial mass and potential. Aldehydes promote glycolysis and inhibit FAO in T cells. Mice deficient in an FAO enzyme in T cells generate more acrolein, a representative aldehyde, enhancing T cell exhaustion and attenuating antitumor immunity. Acrolein is generated partly from mitochondria and damages mitochondrial architecture. Inhibitors of lipid peroxidation or aldehydes enhanced PD-1-blockade by rectifying metabolic imbalance. Therefore, active aldehydes resulting from FAO impairment can cause a vicious cycle of metabolic imbalance that leads to T cell exhaustion.