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<p>Cancer cells utilize tumor-derived exosomes to suppress antitumor immunity. Herein, we identify co-activator-associated arginine methyltransferase 1 (CARM1) as a key regulator of exosome biogenesis and metabolite sorting that inhibiting CD8<sup>+</sup> T cell-mediated antitumor responses. Genetic ablation of CARM1 in breast cancer cells impairs immunosuppressive exosome secretion, enhancing CD8<sup>+</sup> T cell infiltration, proliferation, and effector function. Mechanistically, CARM1 dimethylates apoptosis-linked gene-2 interacting protein X (ALIX) at arginine 757, facilitating its interaction with endosomal sorting complex required transport (ESCRT) components, and promoting tetraspanin-enriched exosome biogenesis. CARM1-dependent ALIX methylation enables selective packaging hypoxanthine into exosomes through direct binding to the ALIX F676 pocket. Exosomal hypoxanthine disrupts inosine metabolism in activated CD8<sup>+</sup> T cells, inhibiting pentose phosphate pathway, glycolysis, nucleotide synthesis, and effector cytokine production. Co-administration of CARM1 inhibitor with inosine significantly enhances tumor-infiltrating CD8<sup>+</sup> T cell cytotoxicity, reduces PD-1<sup>+</sup>TIM-3<sup>+</sup> exhausted CD8<sup>+</sup> T cells, and suppresses tumor growth. These findings establish the CARM1-ALIX-hypoxanthine axis as an immunosuppressive mechanism and suggest that combining CARM1 inhibition with inosine supplementation represent a promising therapeutic strategy for breast cancer.</p>

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CARM1-mediated hypoxanthine-enriched exosomes rewire inosine metabolism and impair CD8+ T cell antitumor function

  • 期刊论文

  • 发表日期：

    2026年1月24日

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  • Jilong Yin,
  • Zhipeng Su,
  • Xi Hu,
  • Haojie Sun,
  • Zenghui Sun,
  • Shuyu Zhou,
  • Wenwen Xu,
  • Ying Xi,
  • Lanlan Liu,
  • Jinwei Zhang,
  • Qian Zhao,
  • Yi Qiao,
  • Jian Zhang,
  • Yingjie Zhang,
  • Ying Xu,
  • Yuchen Fan,
  • Xiaona You,
  • Xiangbo Meng,
  • Fabao Liu

摘要

Cancer cells utilize tumor-derived exosomes to suppress antitumor immunity. Herein, we identify co-activator-associated arginine methyltransferase 1 (CARM1) as a key regulator of exosome biogenesis and metabolite sorting that inhibiting CD8+ T cell-mediated antitumor responses. Genetic ablation of CARM1 in breast cancer cells impairs immunosuppressive exosome secretion, enhancing CD8+ T cell infiltration, proliferation, and effector function. Mechanistically, CARM1 dimethylates apoptosis-linked gene-2 interacting protein X (ALIX) at arginine 757, facilitating its interaction with endosomal sorting complex required transport (ESCRT) components, and promoting tetraspanin-enriched exosome biogenesis. CARM1-dependent ALIX methylation enables selective packaging hypoxanthine into exosomes through direct binding to the ALIX F676 pocket. Exosomal hypoxanthine disrupts inosine metabolism in activated CD8+ T cells, inhibiting pentose phosphate pathway, glycolysis, nucleotide synthesis, and effector cytokine production. Co-administration of CARM1 inhibitor with inosine significantly enhances tumor-infiltrating CD8+ T cell cytotoxicity, reduces PD-1+TIM-3+ exhausted CD8+ T cells, and suppresses tumor growth. These findings establish the CARM1-ALIX-hypoxanthine axis as an immunosuppressive mechanism and suggest that combining CARM1 inhibition with inosine supplementation represent a promising therapeutic strategy for breast cancer.