2026-01-08 京都大学
(A)腫瘍微小環境における CD8⁺T細胞では、ミトコンドリアから活性アルデヒドが生成され、ミトコンドリアの脂肪酸酸化(FAO)機能を低下させる。(B)活性アルデヒドは、解糖系経路を活性化する。(C)活性アルデヒドの蓄積はFAOを低下させ、解糖系を促進することで、代謝疲弊を形成する。図はBioRenderにより作成。
<関連情報>
- https://www.kyoto-u.ac.jp/ja/research-news/2026-01-08
- https://www.kyoto-u.ac.jp/sites/default/files/2026-01/web_2601_Chamoto-bea5cda30cc6bffbaf1b9fccf8a83362.pdf
- https://www.nature.com/articles/s41590-025-02370-w
活性アルデヒドは腫瘍微小環境における代謝変化を介して CD8⁺ T 細胞の疲弊を加速させる Active aldehydes accelerate CD8+ T cell exhaustion by metabolic alteration in the tumor microenvironment
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
Nature Immunology Published:07 January 2026
DOI:https://doi.org/10.1038/s41590-025-02370-w
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.
