Cancer reprograms the remote vascular microenvironment to promote atherosclerosis

Cancer releases a broad repertoire of circulating cytokines and angiogenic factors that remodel distant tissues. However, the remote vascular consequences of tumor-derived inflammatory signaling remain incompletely understood. Our preliminary data suggest that cancer activates a TNF-driven, LRG1-dependent endothelial pro-angiogenic pathway implicated in remote vascular remodeling. We profiled vascular responses to colorectal tumors using bulk and single-cell RNA sequencing of aortic tissues from tumor-bearing versus control mice across diverse backgrounds, endothelial assays stimulated with tumor-conditioned media, O-link proteomics to define tumor-induced circulating mediators, and in vivo perturbation of the TNF-LRG1 axis using a TNF-neutralizing antibody or endothelial-targeted AAV-LRG1 knockdown. Across independent human datasets, we further observed that large cohort studies from both Europe and the United States demonstrate an increased risk of atherosclerotic CVD in cancer survivors, tumor resection is associated with a reduced risk of atherosclerotic events, and biobank tissues from cancer patients display elevated vascular TNF-LRG1 signaling, supporting clinical relevance. In conclusion, cancer upregulates TNF to activate an LRG1-dependent endothelial pathway, driving angiogenesis and vascular remodeling. These findings uncover a previously unrecognized tumor-CVD interaction and identify the TNF-LRG1 axis as a potential therapeutic target to mitigate cancer-induced vascular dysfunction.