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

Cell Death & Differentiation (2026) Cite this article

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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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Fig. 1: CARM1 knockout in tumor cells enhances tumor-infiltrating CD8+ T cell immune responses.
The alternative text for this image may have been generated using AI.
Fig. 2: CARM1 inhibits CD8+ T cell cytotoxicity through regulation of tumor-derived exosome biogenesis.
The alternative text for this image may have been generated using AI.
Fig. 3: ALIX KO partially represents the influence of CARM1 deficiency on tumor growth.
The alternative text for this image may have been generated using AI.
Fig. 4: CARM1 methylates ALIX at Arg757.
The alternative text for this image may have been generated using AI.
Fig. 5: Inhibition of ALIX methylation disrupts exosomes secretion and promotes tumor immune response.
The alternative text for this image may have been generated using AI.
Fig. 6: ALIX directly recruits hypoxanthine and inosine through F676 pocket.
The alternative text for this image may have been generated using AI.
Fig. 7: Hypoxanthine rewires inosine metabolism in CD8+ T cell.
The alternative text for this image may have been generated using AI.
Fig. 8: Administration CARM1 inhibitor and inosine synergistically inhibits tumor growth.
The alternative text for this image may have been generated using AI.

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Data availability

The RNA-seq data have been deposited in Gene Expression Omnibus (GEO) (https://www.ncbi.nlm.nih.gov/geo/), with an accession number GSE308156. The exosomes proteomics data have been deposited in iProX (https://www.iprox.cn) with the dataset identifier PXD071166. The mass spectrometry data of MDA-MB-231 cells analyzed in this study were obtained from our previous study with the dataset identifier PXD005871. Original, uncropped images of blots and gels are provided as Fig. S11. All other raw data generated in this study are available upon request from the corresponding author.

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Acknowledgements

This project is supported by the National Natural Science Foundation of China (NSFC) (No. 82472864, 82173135, 82270150, 82100185, 82470168 and HY2023-18) and supported in part by Young Scholars of Taishan (tsqn202211035, tsqn202211036, tsqn202103007 and tsqn202103169) and Joint Funds of Shandong Natural Science Foundation (No. ZR2024LZL011) and Joint Research Fund Project of Shandong Provincial Third Hospital and Shandong University Qilu Medical College (LHXM2024MS12001). We thank Translational Medicine Core Facility of Shandong University for consultation and instrument availability that supported this work.

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  1. These authors contributed equally: Jilong Yin, Zhipeng Su.

Authors and Affiliations

  1. Advanced Medical Research Institute, Shandong Provincial Third Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China

    Jilong Yin, Zhipeng Su, Xi Hu, Haojie Sun, Zenghui Sun, Shuyu Zhou, Wenwen Xu, Ying Xi, Lanlan Liu, Yi Qiao, Xiangbo Meng & Fabao Liu

  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

    Lanlan Liu, Jinwei Zhang, Jian Zhang, Yingjie Zhang, Xiaona You & Fabao Liu

  3. Department of Hepatology, Qilu Hospital of Shandong University, Jinan, Shandong, China

    Qian Zhao & Yuchen Fan

  4. Department of thyroid and breast surgery, Shandong Provincial Third Hospital, Shandong University, Jinan, Shandong, China

    Ying Xu

  5. Department of Infectious Diseases and Hepatology, The Second Qilu Hospital of Shandong University, Jinan, Shandong, China

    Fabao Liu

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Contributions

F.L., J.Y., and X.Y. conceived the project, designed the experiments, analyzed the data, and wrote the manuscript. J.Y. conducted the experiments with technical assistance from Z.S., W.X., Y.X., L.L., Q.Z., Y.Q., and J.Z. X.H. performed the RNA-seq data analysis and contributed to manuscript editing. Z.S., H.S. and S.Z. were responsible for T cell activation assays and tumor-infiltrating T cell analysis. X.M. directed and supervised the CD8+ T cell-based antitumor studies. J.Z. and Y.Z. performed the molecular docking. F.L., X.M., X.Y., Y.F., and Y.X. supervised all aspects of the study. All authors reviewed the results and provided critical feedback on the manuscript.

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Correspondence to Ying Xu, Yuchen Fan, Xiaona You, Xiangbo Meng or Fabao Liu.

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Yin, J., Su, Z., Hu, X. et al. CARM1-mediated hypoxanthine-enriched exosomes rewire inosine metabolism and impair CD8+ T cell antitumor function. Cell Death Differ (2026). https://doi.org/10.1038/s41418-026-01673-1

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