Review discusses translational potential of macrophage-state signatures for atherosclerosis risk stratification and therapeutic targeting.

Human atherosclerosis is increasingly recognized as a spatially organized inflammatory disease in which macrophages act as central regulators of lesion evolution rather than as a uniform foam-cell population. Recent single-cell and spatial profiling studies have redefined plaque macrophages as reproducible state programs, including inflammatory, interferon-responsive, lipid-associated, foamy, resident-like, and reparative phenotypes, each embedded within distinct microanatomic niches and multicellular communication networks. These programs are not merely descriptive, but are linked to clinically relevant features such as symptomatic disease, necrotic core expansion, fibrous cap thinning, extracellular matrix remodeling, and recurrent vascular risk. At the same time, the field remains limited by heterogeneity in plaque procurement, anatomic annotation, computational integration, and state nomenclature, which complicates cross-study comparison and obscures biological concordance. This review summarizes the recent advances in human plaque single-cell, spatial transcriptomic, and integrative multi-omics studies to outline the emerging architecture of macrophage states in atherosclerosis. We examine how atlas-scale frameworks connect state definition with spatial localization, regulatory circuitry, and lesion behavior, and discuss how these insights refine mechanistic understanding of plaque progression. We further highlight the translational potential of macrophage-state signatures for risk stratification, molecular imaging, and therapeutic targeting. A coherent human plaque macrophage atlas offers a conceptual and practical framework for moving from descriptive heterogeneity toward clinically actionable biology in atherosclerotic disease.