2. Academic Validation
  3. CARM1-mediated hypoxanthine-enriched exosomes rewire inosine metabolism and impair CD8+ T cell antitumor function

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

  • Cell Death Differ. 2026 Jan 24. doi: 10.1038/s41418-026-01673-1.
Jilong Yin # 1,  Zhipeng Su # 1,  Xi Hu 1,  Haojie Sun 1,  Zenghui Sun 1,  Shuyu Zhou 1,  Wenwen Xu 1,  Ying Xi 1,  Lanlan Liu 1 2,  Jinwei Zhang 2,  Qian Zhao 3,  Yi Qiao 1,  Jian Zhang 2,  Yingjie Zhang 2,  Ying Xu 4,  Yuchen Fan 5,  Xiaona You 6,  Xiangbo Meng 7,  Fabao Liu 8 9 10
Affiliations

Affiliations

  • 1 Advanced Medical Research Institute, Shandong Provincial Third Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China.
  • 2 State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China.
  • 3 Department of Hepatology, Qilu Hospital of Shandong University, Jinan, Shandong, China.
  • 4 Department of thyroid and breast surgery, Shandong Provincial Third Hospital, Shandong University, Jinan, Shandong, China. [email protected].
  • 5 Department of Hepatology, Qilu Hospital of Shandong University, Jinan, Shandong, China. [email protected].
  • 6 State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China. [email protected].
  • 7 Advanced Medical Research Institute, Shandong Provincial Third Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China. [email protected].
  • 8 Advanced Medical Research Institute, Shandong Provincial Third Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China. [email protected].
  • 9 State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China. [email protected].
  • 10 Department of Infectious Diseases and Hepatology, The Second Qilu Hospital of Shandong University, Jinan, Shandong, China. [email protected].
  • # Contributed equally.
PMID: 41580530 DOI: 10.1038/s41418-026-01673-1
Abstract

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.

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