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Purine salvage pathway protects CD8 + T cells from metabolic stress

Nature Immunology, Published online: 13 April 2026; doi:10.1038/s41590-026-02491-w Tajima et al. show that a transient or continuous high-fat diet induces metabolic changes in CD8+ T cells that lead to increased vulnerability to ferroptosis and reduced antitumor responses.

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Nature Immunology, Published online: 13 April 2026; doi:10.1038/s41590-026-02491-w Tajima et al. show that a transient or continuous high-fat diet induces metabolic changes in CD8+ T cells that lead to increased vulnerability to ferroptosis and reduced antitumor responses.

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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. Access to this article via Institution of Civil Engineers Library is not available. The RNA-sequencing datasets are publicly available in the Gene Expression Omnibus with accession code GSE276598 . The proteomics data are deposited to the ProteomeXchange Consortium via the jPOST 54 partner repository with the dataset identifier JPST003781 ( PXD063309 for ProteomeXchange). Lipidome data are available from DROPmet ( https://prime.psc.riken.jp/menta.cgi/prime/drop_index ) under accession number DM0064. Source data are provided with this paper. Lichtenstein, P. et al. Environmental and heritable factors in the causation of cancer–analyses of cohorts of twins from Sweden, Denmark, and Finland. N. Engl. J. Med. 343 , 78–85 (2000). David, L. A. et al. Diet rapidly and reproducibly alters the human gut microbiome. Nature 505 , 559–563 (2014). Schulz, M. D. et al. High-fat-diet-mediated dysbiosis promotes intestinal carcinogenesis independently of obesity. Nature 514 , 508–512 (2014). Furman, D. et al. Chronic inflammation in the etiology of disease across the life span. Nat. Med. 25 , 1822–1832 (2019). Khandekar, M. J., Cohen, P. & Spiegelman, B. M. Molecular mechanisms of cancer development in obesity. Nat. Rev. Cancer 11 , 886–895 (2011). Wang, Z. et al. Paradoxical effects of obesity on T cell function during tumor progression and PD-1 checkpoint blockade. Nat. Med. 25 , 141–151 (2019). Hata, M. et al. Past history of obesity triggers persistent epigenetic changes in innate immunity and exacerbates neuroinflammation. Science 379 , 45–62 (2023). Hemade, A. & Salameh, P. Metabolic scarring: the persistent impact of past obesity on long-term metabolic health despite weight loss. Endocrinol. Diabetes Metab. 8 , e70086 (2025). Yang, W. S. et al. Peroxidation of polyunsaturated fatty acids by lipoxygenases drives ferroptosis. Proc. Natl Acad. Sci. USA 113 , E4966–E4975 (2016). Rashida Gnanaprakasam, J. N., Wu, R. & Wang, R. Metabolic reprogramming in modulating T cell reactive oxygen species generation and antioxidant capacity. Front. Immunol. 9 , 1075 (2018). Eichwald, T. et al. Tetrahydrobiopterin: beyond its traditional role as a cofactor. Antioxidants https://doi.org/10.3390/antiox12051037 (2023). Cronin, S. J. F. et al. The metabolite BH4 controls T cell proliferation in autoimmunity and cancer. Nature 563 , 564–568 (2018). Dierge, E. et al. Peroxidation of n-3 and n-6 polyunsaturated fatty acids in the acidic tumor environment leads to ferroptosis-mediated anticancer effects. Cell Metab. 33 , 1701–1715 (2021). Li, J., Wu, H., Liu, Y. & Yang, L. High fat diet induced obesity model using four strainsof mice: Kunming, C57BL/6, BALB/c and ICR. Exp. Anim. 69 , 326–335 (2020). Harayama, T. & Riezman, H. Understanding the diversity of membrane lipid composition. Nat. Rev. Mol. Cell Biol. 19 , 281–296 (2018).

Original source: https://www.nature.com/articles/s41590-026-02491-w