Diabetes is a rapidly escalating global health crisis, affecting over 415 million individuals worldwide and projected to reach 642 million by 2040, with more than 75% of cases occurring in low- and middle-income countries (Ogurtsova et al., 2017). Cardiovascular disease (CVD) remains the leading cause of mortality in diabetes, accounting for approximately 32% of deaths, largely driven by accelerated atherosclerosis and chronic vascular inflammation (Einarson et al., 2018). The diabetic vasculature represents a uniquely hostile microenvironment in which persistent hyperglycemia, insulin resistance, and dyslipidemia induce oxidative stress, endothelial dysfunction, and sustained immune activation. While metabolic drivers of atherogenesis have been extensively characterized, the immune regulatory mechanisms that sustain vascular inflammation in diabetes remain incompletely understood.

Emerging evidence identifies immune checkpoint dysfunction as a central mechanistic link between metabolic stress and vascular inflammation. Key inhibitory regulators of T cell activation, including programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1), and cytotoxic T-lymphocyte–associated protein 4 (CTLA-4), are significantly impaired under hyperglycemic and insulin-resistant conditions, leading to unchecked T cell activation and loss of immune homeostasis (Bu et al., 2011; Patsoukis et al., 2020). Experimental studies demonstrate that disruption of PD-1/PD-L1 signaling accelerates atherosclerotic plaque formation and enhances vascular inflammation, supporting a protective role for these pathways in maintaining arterial integrity (Gotsman et al., 2007; Bu et al., 2011).

Clinical observations further reinforce this paradigm. Large-scale studies of patients receiving immune checkpoint inhibitors (ICIs) for cancer therapy report a significantly increased risk of major adverse cardiovascular events, including myocardial infarction and stroke, with hazard ratios exceeding 3.0 in high-risk populations (Drobni et al., 2020). Notably, this risk is amplified in individuals with pre-existing diabetes or metabolic syndrome, suggesting that baseline checkpoint impairment may predispose to heightened vascular injury when these pathways are further disrupted (Lyon et al., 2018).

In parallel, patients with diabetes exhibit reduced expression of immune checkpoint molecules, with the degree of suppression correlating with glycemic burden, systemic inflammation, and cardiovascular risk profiles (Wang et al., 2019). These findings support the concept that diabetes represents a systemic immune checkpoint–deficient state, contributing to persistent vascular inflammation and plaque instability.

This review proposes a unifying translational framework in which immune checkpoint dysfunction serves as a central driver of diabetes-accelerated atherosclerosis. We integrate evidence from metabolic disease, immunology, and cardiovascular research to demonstrate how autoimmune checkpoint failure in type 1 diabetes and metabolism-driven checkpoint suppression in type 2 diabetes converge on a shared metabolic–epigenetic axis that sustains chronic inflammation. Building on this framework, we highlight emerging therapeutic strategies, including PD-L1 agonism, CTLA-4 mimetics, and targeted gene therapy approaches, aimed at restoring immune tolerance within the vascular microenvironment while minimizing systemic immunosuppression. Finally, we outline clinically actionable biomarker and imaging strategies to enable early-phase translational studies and precision-based patient selection.