Macrophages: sentinels, warriors, and healers

Abstract Macrophages are versatile innate immune cells that act as sentinels, warriors, and healers in virtually every tissue. This review synthesizes current insights into their developmental origins and the organ-specific cues that imprint diverse tissue-resident and monocyte-derived programs. We detail how pattern-recognition pathways, metabolic and epigenetic rewiring, and environmental signals govern macrophage plasticity, steering transitions between pro-inflammatory and reparative phenotypes during homeostasis, infection, and sterile injury. Dysregulated macrophage responses drive chronic inflammatory, autoimmune, metabolic, neurodegenerative, and neoplastic diseases; inter-individual variability rooted in genetic polymorphisms and enhancer landscapes further modulates susceptibility. Advances in single-cell and spatial multi-omics are redefining macrophage subsets and exposing disease-associated states, while approaches such as checkpoint blockade, chimeric antigen receptor macrophages, nanoparticles, metabolic modulators, and pro-resolving mediators showcase the therapeutic promise of re-programming these cells. Remaining challenges include integrating the layered genetic, metabolic, and microenvironmental inputs that dictate macrophage fate. Addressing these gaps will unlock precision strategies that harness macrophage plasticity to combat infection, resolve inflammation, repair tissue, and augment anti-tumor immunity.