Abstract

This review explores the dual roles of lipid-laden macrophages (LL-Macs) in inflammation, atherosclerosis and cancer, emphasizing both their shared and divergent functions across physiological and pathological conditions. Lipid metabolism regulates the polarization of macrophages in homeostasis and inflammation. In atherosclerosis, LL-Macs contribute to plaque formation and inflammation, while in cancer, LL-Macs play crucial roles in immune suppression and tumor progression. The article outlines the molecular mechanisms driving macrophage lipid accumulation in each of these scenarios and how the process is influenced by the distinct local microenvironments in inflammation, atherosclerosis and cancer. Single-cell RNA sequencing (scRNA-seq) studies have identified both common and unique gene signatures between LL-Macs in atherosclerosis and cancer, reflecting the varying microenvironmental cues that shape macrophage function and disease outcomes. Finally, we examine lipid-modulating strategies in atherosclerosis, assess their potential in cancer treatment, and highlight research gaps for developing new LL-Macs targeted therapies in cancer.