Macrophage biology and immunoregulation in health and disease

Abstract Macrophages are versatile immune cells that maintain tissue homeostasis and shape disease progression through continuous adaptation to the local environment. Recent advances in single-cell, spatial, and multiomics technologies have revealed extensive diversity in tissue-specific macrophage identities and their adaptation to physiological and pathological contexts. Emerging evidence indicates that macrophage behavior emerges from the coordinated integration of ontogenetic imprinting, environmental sensing, metabolic rewiring, and epigenetic remodeling. These interconnected layers collectively determine macrophage responses in inflammatory diseases, neurodegeneration, and cancer, creating both challenges and opportunities for therapeutic intervention. In this review, we provide an overview of recent mechanistic insights into the molecular circuits governing macrophage plasticity and function and discuss how this evolving framework can inform next-generation macrophage-based therapeutic strategies to restore immune homeostasis and improve disease outcomes.