Purine salvage pathway protects CD8+ T cells from metabolic stress PMID: 41974963

Target-related Cytokines

2026-09-23

Purine salvage pathway protects CD8+ T cells from metabolic stress

Nat Immunol. 2026 May;27(5):1026-1038. doi: 10.1038/s41590-026-02491-w.

Masaki Tajima ¹ , He Hao ^# ² ³ ⁴ , Baihao Zhang ^# ⁵ , Yuta Matsuoka ^# ⁶ , Kazuhiro Sonomura ⁷ , Koshi Imami ⁸ , Yosuke Isobe ⁹ , Rae Maeda ⁶ , Yu-Hsien Lin ² , Akihiro Shimba ² , Ryoma Kato ² , Pedro Henrique Costa Cruz ² , Sayaka Washizu ² , Yosuke Ikejiri ² , Akiyo Morinibu ² , Clive Steven Barker ¹⁰ , Jun Seita ¹⁰ , Yibo Wu ¹¹ ¹² , Satomi Ito ⁵ , Seiko Narushima ⁵ , Rei Nakano ⁵ , Mikako Maruya ⁵ , Wakana Kobayashi ⁵ , Sai Shanmukha Priya Narayanan ² , Jumana Shaheen ² , Hiroyuki Neyama ⁶ , Ken-Ichi Yamada ¹³ , Makoto Arita ⁹ ¹⁴ , Yuki Sugiura ⁶ ¹⁵ , Sidonia Fagarasan ¹⁶ ¹⁷

Affiliations

1. Division of Integrated High-Order Regulatory Systems, Center for Cancer Immunotherapy and Immunobiology, Graduate School of Medicine, Kyoto University, Kyoto, Japan. [email protected].
2. Division of Integrated High-Order Regulatory Systems, Center for Cancer Immunotherapy and Immunobiology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
3. Department of Internal Medicine, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China.
4. Cancer Center, Shanxi Bethune Hospital, Third Hospital of Shanxi Medical University, Taiyuan, China.
5. Laboratory for Mucosal Immunity, Center for Integrative Medical Sciences, RIKEN, Yokohama, Japan.
6. Multi Omics Platform, Center for Cancer Immunotherapy and Immunobiology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
7. Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto University, Kyoto, Japan.
8. Proteome Homeostasis Research Unit, Center for Integrative Medical Sciences, RIKEN, Yokohama, Japan.
9. Laboratory for Metabolomics, Center for Integrative Medical Sciences, RIKEN, Yokohama, Japan.
10. Laboratory for Integrative Genomics, Center for Integrative Medical Sciences, RIKEN, Yokohama, Japan.
11. YCI Laboratory for Next-Generation Proteomics, Center for Integrative Medical Sciences, RIKEN Yokohama Institute, Yokohama, Japan.
12. Department of Biomedical Sciences, University of Lausanne, Lausanne, Switzerland.
13. Department of Molecular Pathobiology, Faculty of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.
14. Division of Physiological Chemistry and Metabolism, Graduate School of Pharmaceutical Sciences, Keio University, Tokyo, Japan.
15. Human Biology-Microbiome-Quantum Research Center (WPI-Bio2Q), Keio University, Tokyo, Japan.
16. Division of Integrated High-Order Regulatory Systems, Center for Cancer Immunotherapy and Immunobiology, Graduate School of Medicine, Kyoto University, Kyoto, Japan. [email protected].
17. Laboratory for Mucosal Immunity, Center for Integrative Medical Sciences, RIKEN, Yokohama, Japan. [email protected].
# Contributed equally.

Abstract

Metabolic stress from a high-fat diet (HFD) impairs antitumor immunity through persistent metabolic rewiring, but its effects and long-term impact on CD8⁺ T cell metabolism remain unknown. Here, we found that even temporary exposure to a HFD impaired antitumor immunity 10 weeks after reversion to a normal diet. This was due to lasting metabolome changes that included enrichment in Phospholipids sensitive to peroxidation and depletion of Antioxidants, affecting the survival and function of CD8⁺ T cells. Under oxidative stress, CD8⁺ T cells utilized the xanthine salvage pathway to produce Guanosine triphosphate, enhancing the amount of tetrahydrobiopterin. Xanthine supplementation reduced lipid peroxidation in tumor-draining Lymph Nodes and improved antitumor immunity in mice previously on a HFD. Our data indicate that metabolic stress in CD8⁺ T cells persists long after restoration of a balanced diet, and manifests as vulnerability to Ferroptosis, which could be mitigated by replenishing biopterins through the xanthine salvage pathway.