Accelerated atherosclerosis associated with immune checkpoint inhibitors: a systematic review and meta-analysis of pre-clinical studies

Background: Patients with cancer treated with immune checkpoint inhibitors are at increased risk of myocardial infarction and ischemic stroke. The mechanism is incompletely understood but may involve accelerated atherosclerosis due to enhanced inflammation. Pre-clinical studies may provide insight in these mechanisms. Aim: To assess the effects of modulating co-inhibitory immune checkpoint proteins on atherosclerosis progression in animal models. Methods: A systematic review was performed in MEDLINE, Embase, Web of Science, and Scopus up to March 2025. Animal studies were included if the effect of modulation of programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1), cytotoxic T-lymphocyte associated protein 4 (CTLA-4), and/or lymphocyte-activation gene 3 (LAG-3) on atherosclerotic plaque size was evaluated. Secondary outcomes were plaque composition and systemic inflammation. The ratios of means (RoM) across the studies were pooled in a random effects meta-analysis. Risk of bias was assessed using the SYRCLE tool, focusing on randomization, blinding, and completeness of outcome reporting. Results: Fourteen eligible studies were included. All studies used an atherosclerotic mouse model (ApoE−/−, Ldlr−/−, ApoE3∗Leiden, or AAV8-PCSK9) and either evaluated pharmacological or genetic modulation of co-inhibitory immune checkpoint proteins. Upon inhibition, atherosclerotic plaque size in the aorta was 53 % higher in exposed mice compared to control mice (RoM, 1.53; 95 % CI, 1.29–1.83; I2 = 89 %). Plaque composition was predominantly characterized by a greater abundance of CD4+ T cells, CD8+ T cells, and macrophages. Studies stimulating co-inhibitory immune checkpoint proteins corroborated these findings and demonstrated that atherosclerotic plaque size was reduced by 28 % in treated mice compared to controls (RoM, 0.72; 95 % CI, 0.65–0.80; I2 = 85 %). This reduction was paralleled by a decrease in the number of macrophages and T cells in plaques. Conclusion: Immune checkpoint inhibition leads to increased plaque inflammation and a significant increase in murine atherosclerotic plaque size. These changes may reflect the cause of the increased risk of myocardial infarction and ischemic stroke in patients treated with immune checkpoint inhibitors.