2026年1月13日 / 最終更新日 : 2026年1月13日 ad_y ニュース

2026年 新着論文 3　細胞情報学分野から論文が発表されました

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

Nat Immunol. 2026 Jan 7. doi: 10.1038/s41590-025-02370-w. Online ahead of print.

Authors

Yasuharu Haku #  1   2 , Koji Kitaoka #  1 , Koki Ichimaru  1   3 , Tomoko Hirano  1   4 , Jun Wang  1 , Kazuhiro Sonomura  5 , Asuka Maruo  5 , Shuhei Hirose  1 , Yu Wang  1 , Katsuhiro Ito  1   6 , Tomohiro Kozuki  1   7 , Keiko Yurimoto  1 , Mai Kiyono  1 , Hidetaka Kosako  8 , Toshi Menju  9 , Hiroshi Date  9 , Takashi Kobayashi  6 , Koichi Omori  2   10 , Tomonori Yaguchi  1   3   11 , Tasuku Honjo  1 , Kenji Chamoto  12   13

Affiliations

  • 1 Department of Immunology and Genomic Medicine, Center for Cancer Immunotherapy and Immunobiology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
  • 2 Department of Otolaryngology-Head and Neck Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
  • 3 Department of Immuno-Oncology PDT, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
  • 4 Department of Dermatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
  • 5 Technology Research Laboratory, Shimadzu Corp., Nakagyo-ku, Japan.
  • 6 Department of Urology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
  • 7 Department of Rheumatology and Clinical Immunology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
  • 8 Division of Cell Signaling, Institute of Advanced Medical Sciences, Tokushima University, Tokushima, Japan.
  • 9 Department of Thoracic Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
  • 10 Department of Head and Neck Oncology and Innovative Treatment, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
  • 11 Department of Immune metabolism, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
  • 12 Department of Immunology and Genomic Medicine, Center for Cancer Immunotherapy and Immunobiology, Graduate School of Medicine, Kyoto University, Kyoto, Japan. chamoto.kenji.4w@kyoto-u.ac.jp.
  • 13 Department of Immuno-Oncology PDT, Graduate School of Medicine, Kyoto University, Kyoto, Japan. chamoto.kenji.4w@kyoto-u.ac.jp.
# Contributed equally.

Abstract

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.

Conflict of interest statement

Competing interests: T. Honjo and K.C. received research funding from Shimadzu Corporation. All other authors declare no competing interests.

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