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CARM1-mediated hypoxanthine-enriched exosome biogenesis rewires inosine metabolism of CD8+ T cells and impairs their antitumor ability

ABSTRACT: Cancer cells engage in complex interactions with tumor infiltrating immune cells to overcome barriers to tumor progression. Targeting biogenesis of tumor-derived exosomes is a promising strategy for disrupting intracellular communication. Herein, we identify co-activator-associated arginine methyltransferase 1 (CARM1) as a key regulator of tumor-derived exosome biogenesis and metabolite sorting, thereby inhibiting CD8+ T cell-mediated antitumor immunity. Genetic ablation of CARM1 in breast cancer cells impairs the secretion of immunosuppressive exosomes, leading to enhanced CD8+ T cell infiltration, proliferation, and effector function in tumors. Mechanistically, CARM1 methylates apoptosis-linked gene-2 interacting protein X (ALIX) at Arg757, facilitating its interaction with endosomal sorting complex required transport (ESCRT) components, and promoting the biogenesis of tetraspanin-enriched exosomes. CARM1-dependent ALIX methylation enables selective packaging hypoxanthine into exosomes through direct binding to ALIX at the F676 pocket. Excess hypoxanthine disrupts inosine metabolism in the activated CD8+ T cells, inhibiting glycolysis, nucleotide synthesis, and effector cytokine production. Co-administration of CARM1 inhibitor with inosine significantly increases tumor infiltrating CD8+ T cell cytotoxicity, reduces exhaustion markers programmed cell death 1 and T cell immunoglobulin mucin 3 (PD-1+TIM-3+) expression and suppresses tumor growth. Collectively, the CARM1-ALIX-hypoxanthine axis functions as immunosuppressive mechanism in tumor growth, and targeting CARM1 combined with inosine supplement may represent a novel therapeutic regimen for breast cancer therapy.

ORGANISM(S): Mus musculus

PROVIDER: GSE308156 | GEO | 2026/01/23

REPOSITORIES: GEO

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Project description:BACKGROUND: Heart failure (HF) is one of the leading causes of mortality worldwide. Extracellular vesicles (EVs) including small EVs, or exosomes and their molecular cargo are known to modulate cell to cell communication during multiple cardiac diseases. However, the role of systemic EV biogenesis inhibition in the models of HF is not well documented and remains unclear. METHODS: We investigated the role of circulating exosomes during cardiac dysfunction and remodeling in a mouse transverse aortic constriction (TAC) model of HF. Importantly, we investigate the efficacy of Tipifarnib (Tip), a recently identified exosome biogenesis inhibitor that targets the critical proteins (Rab27a, nSmase2 and Alix) involved in exosome biogenesis for this mouse model of HF. In this study, 10-week-old male mice underwent TAC surgery, were randomly assigned to groups with and without Tip treatment (10 mg/kg three times/week) and monitored for 8 weeks and a comprehensive assessment was conducted through performed echocardiographic, histological, and biochemical studies. RESULTS: TAC significantly elevated circulating plasma exosomes and markedly increased cardiac left ventricular (LV) dysfunction, cardiac hypertrophy, and fibrosis. Furthermore, injection of plasma exosomes from TAC mice induced LV dysfunction and cardiomyocyte hypertrophy in uninjured mice without TAC. On the contrary, treatment of Tip in TAC mice reduced circulating exosomes to baseline and remarkably improved LV functions, hypertrophy, and fibrosis. Tip treatment also drastically altered the miRNA profile of circulating post-TAC exosomes, including miR331-5p which was highly downregulated both in TAC circulating exosomes and in TAC cardiac tissue. Mechanistically, miR331-5p is crucial for inhibiting fibroblast-to-myofibroblast transition by targeting HOXC8, a critical regulator of fibrosis. Tipifarnib treatment in TAC mice upregulated the expression of miR331-5p that acts as potent repressor for one of the fibrotic mechanisms mediated by HOXC8. CONCLUSIONS: Our study underscores the pathological role of exosomes in HF and fibrosis in response to pressure overload. Tipifarnib mediated inhibition of exosome biogenesis and cargo sorting may serve as a viable strategy to prevent progressive cardiac remodeling to HF.

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CARM1-mediated hypoxanthine-enriched exosome biogenesis rewires inosine metabolism of CD8+ T cells and impairs their antitumor ability

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