Cell-death-driven plaque evolution: macrophage fate and opportunities for targeted therapy

Atherosclerosis (AS) is a lipid-driven chronic inflammatory disease in which pathological progression is profoundly regulated by macrophage fate determination mechanisms. This review explores how macrophages derived from hemogenic endothelial cells and bone marrow contribute to disease development, functioning either as tissue-resident cells or via systemic circulation. These macrophages drive the plaque progression via three major cellular fates: foam cell formation, polarization, and programmed cell death. Impaired cholesterol efflux, together with enhanced scavenger receptor expression induced by M1 macrophage polarization, are key features of macrophage-derived foam cells. The dichotomous polarization of macrophages into M1 and M2 phenotypes forms the basis of their complex regulatory roles within the plaque microenvironment. Moreover, recent advances in sequencing technologies have uncovered additional macrophage subsets, whose specific contributions to AS progression remain to be fully elucidated. Adopting a framework that links the macrophage life cycle with AS, this review discusses the critical roles of macrophages in AS progression from the perspectives of classical (M1/M2) and various non-classical cell classifications, by delineating the macrophage life cycle from origin to distinct cellular fates within the plaque environment. Concurrently, we summarize potential therapeutic strategies targeting these processes, including metabolic reprogramming, immunomodulation, epigenetic regulation, and innovative drug delivery systems, which provide multi-layered approaches for plaque stabilization while remaining subject to substantial limitations. Overall, we emphasize the unique fate trajectories of different macrophage lineages in AS progression, their multifaceted impact on AS pathological outcomes, and recent advances in potential targeted therapeutic strategies.