Tumor-driven arginine depletion induces T-cell metabolism reprogramming to suppress atherosclerosis in colorectal cancer.

The coexistence of atherosclerosis and cancer is increasingly common, yet the influence of tumors on atherogenesis remains poorly understood. In this study, we investigated the impact of colorectal cancer (CRC) on atherosclerosis and elucidated the underlying mechanisms. We analyzed clinical data from patients with concurrent atherosclerosis and CRC and established three murine models of atherosclerosis comorbidity: ApoE-/- and Ldlr-/- mice bearing subcutaneous MC38 tumors, and APCmin/+ApoE-/- mice with spontaneous intestinal adenomas. We found that both patients and mice with concurrent tumors exhibited reduced plaque burden and enhanced plaque stability. Integrative multi-omics analysis comprising single-cell RNA sequencing, spatial transcriptomics, metabolomics, and bulk RNA sequencing revealed that tumors systemically deplete arginine, leading to adaptive metabolic reprogramming of intraplaque T cells toward an oxidative phosphorylation (OXPHOS)-dominant state. This metabolic shift was associated with reduced cytotoxic T-cell infiltration, suppressed pro-inflammatory effector programs, and weakened T cell-macrophage interactions, collectively establishing a low-inflammatory plaque microenvironment. Importantly, dietary arginine supplementation restored T-cell activation and reversed the CRC-mediated atheroprotective effects. These findings reveal a critical role of T-cell immunometabolic reprogramming in cancer-atherosclerosis comorbidity, demonstrate the pronounced context-dependent effects of arginine in advanced atherosclerosis, and highlight plaque-targeted immunometabolic interventions as a promising strategy to modulate plaque progression and stability.