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<p>Metabolic stress from a high-fat diet (HFD) impairs antitumor immunity through persistent metabolic rewiring, but its effects and long-term impact on CD8<sup>+</sup> 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<sup>+</sup> T cells. Under oxidative stress, CD8<sup>+</sup> 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<sup>+</sup> 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.</p>

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Purine salvage pathway protects CD8+ T cells from metabolic stress

  • 期刊论文

  • 发表日期：

    2026年4月13日

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  • Masaki Tajima,
  • He Hao,
  • Baihao Zhang,
  • Yuta Matsuoka,
  • Kazuhiro Sonomura,
  • Koshi Imami,
  • Yosuke Isobe,
  • Rae Maeda,
  • Yu-Hsien Lin,
  • Akihiro Shimba,
  • Ryoma Kato,
  • Pedro Henrique Costa Cruz,
  • Sayaka Washizu,
  • Yosuke Ikejiri,
  • Akiyo Morinibu,
  • Clive Steven Barker,
  • Jun Seita,
  • Yibo Wu,
  • Satomi Ito,
  • Seiko Narushima,
  • Rei Nakano,
  • Mikako Maruya,
  • Wakana Kobayashi,
  • Sai Shanmukha Priya Narayanan,
  • Jumana Shaheen,
  • Hiroyuki Neyama,
  • Ken-ichi Yamada,
  • Makoto Arita,
  • Yuki Sugiura,
  • Sidonia Fagarasan

摘要

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.