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Immune checkpoint inhibitors targeting programmed cell death ligand 1 (PD-L1) have transformed cancer therapy but have been linked to increased cardiovascular risk, particularly atherosclerosis (AS). This study hypothesized that anti-PD-L1 therapy promotes atherosclerosis progression by modulating macrophage phenotypes and enhancing foam cell formation via gene-level changes. Single-cell RNA sequencing (scRNA-seq) analysis of macrophages post-anti-PD-L1 immunotherapy was conducted using the GSE169246 dataset. Differential expression, GO/KEGG enrichment, and transcription factor analyses were performed. Cellular communication patterns were examined, and in vitro validation included foam cell assays and protein-level assessments. Anti-PD-L1 treatment promoted a shift toward pro-inflammatory M1 macrophages, increased foam cell formation, and upregulated EGR1 and HSP90AB1. These gene changes correlated with altered cellular interaction patterns, particularly between macrophages and endothelial cells. PD-L1 inhibition reprograms macrophage behavior through EGR1 and HSP90AB1-mediated pathways, driving M1 polarization and foam cell development. These findings reveal a mechanistic link between immunotherapy and AS progression and underscore the need for cardiovascular monitoring in patients undergoing PD-L1 blockade.