Abstract Body (Do not enter title and authors here): Immune checkpoint inhibitor (ICI) therapies substantially increase the risk of atherosclerotic cardiovascular events in cancer survivors. Here, we mapped the expression of immune checkpoints (ICs) within human atherosclerotic plaques, unraveling an intricate local network of immune cell-cell interactions in the context of relevant comorbidities like dyslipidemia and diabetes. Our findings identified a population of mature, regulatory CCR7⁺ FSCN1⁺ dendritic cells as pivotal orchestrators of IC-mediated signaling within human and murine plaques, a function akin to their role in tumor environments. In clinical cohorts, type 2 diabetes diminished CCR7⁺ FSCN1⁺ dendritic cells within atherosclerotic plaques and dampened interactions steered by PD-1 or CTLA4 consistently across immune cell subpopulations. This effect was also present and further decreased by lipid lowering in the circulation, where CD86–CTLA4 was among the most prominent IC pairs signaling between regulatory T cells and myeloid populations including CCR7⁺ FSCN1⁺ dendritic cells. These findings underline the vulnerability of atherosclerotic plaques to cancer immunotherapies and underscore the critical impact of cardiometabolic disease and lipid-lowering strategies on the atherosclerotic IC landscape, offering a framework toward the reshaping of clinical approaches.