A research team led by CCII Program-specific Professor Kenji Chamoto from the Department of Immunogenomics, doctoral students Yasuharu Shira and Koji Kitaoka, has uncovered a metabolic mechanism that drives the exhaustion of intratumoral CD8⁺ T cells, which are essential for the effectiveness of cancer immunotherapy. Their analysis from the perspective of cellular energy metabolism revealed that terminally exhausted T cells within tumors fall into a state of “metabolic exhaustion,” characterized by excessive dependence on glycolysis and a marked reduction in fatty acid oxidation (FAO).
The study further demonstrated that the accumulation of reactive aldehydes accelerates T‑cell exhaustion, promotes terminal differentiation, and significantly weakens antitumor immunity. Importantly, the researchers confirmed that drugs capable of suppressing reactive aldehydes and lipid peroxidation can enhance the therapeutic efficacy of PD‑1 blockade.
These findings suggest that combining PD‑1 inhibitors with new therapeutic strategies aimed at disrupting this metabolic vicious cycle may lead to further improvements in cancer immunotherapy.
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This research was published online in Nature Immunology on January 7, 2026.
Publication details
【Journal】Nature Immunology
【Title】Active aldehydes accelerate CD8+ T cell exhaustion by metabolic alteration in the tumor microenvironment
【Authors】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# (*Co-first author 、#Corresponding author)
【Date of publication】January 7, 2026（Online）