Protective Effect of Red Yeast Rice on Immune Checkpoint Inhibitors‐Related Atherosclerotic Progression Through Inhibiting Macrophage Inflammatory Response and T Lymphocytes Infiltration

ABSTRACT Immune checkpoint inhibitors (ICIs) have prolonged cancer survival but exacerbated atherosclerotic cardiovascular disease (ASCVD). This research aims to interrogate the underlying mechanism of ICIs‐related atherosclerotic progression and the potential protective effect of Red Yeast Rice (RYR) on it. A tumor‐bearing atherosclerotic (TB‐AS) mouse model was established by subcutaneously injecting MC38 cells in male ApoE −/− mice fed a high‐fat diet (HFD). Intraperitoneal anti‐PD‐1 antibody (αPD‐1) with/without dietary RYR supplementation was administered during the model. Serum was separated for lipid and inflammation evaluation. Plaque assessment was quantified by histological staining. Bone marrow‐derived macrophages (BMDMs) were isolated, incubated in growth medium containing 5% serum from the mice model, and treated with ox‐LDL and RYR. Cell viability was accessed by CCK8 assay. Lipid staining was employed to assess lipid droplet accumulation. The apoptosis and polarization of BMDMs were analyzed using flow cytometry. Cytokine levels were determined by luminex multiplex assay. And finally, western blot was conducted for mechanism investigation. αPD‐1 significantly increased atherosclerotic lesion area, plaque lipid content, and macrophage/T‐cell infiltration versus untreated TB‐AS controls. These effects coincided with elevated pro‐inflammatory cytokines/chemokines and reduced anti‐inflammatory mediators. RYR co‐treatment attenuated these αPD‐1‐induced pro‐atherogenic changes. In vitro, compared with serum from TB‐AS mice, BMDMs cultured with serum from αPD‐1‐treated TB‐AS mice exhibited reduced cell viability, elevated pro‐inflammatory cytokine levels in culture supernatants, enhanced M1 polarization, and increased apoptosis levels. All these phenotypic changes were reversed by RYR treatment. Mechanistically, RYR significantly inhibited the RhoA‐mediated activation of NF‐κB and MAPK signaling, thereby suppressing the αPD‐1‐induced inflammatory response in BMDMs. αPD‐1 promotes ASCVD progression by enhancing macrophage inflammation and T‐cell recruitment within plaques. RYR mitigates these effects through RhoA inhibition, suggesting its therapeutic potential for improving cardiovascular outcomes in ICIs‐treated cancer patients with ASCVD.