Macrophages as Multifaceted Orchestrators of Tissue Repair: Bridging Inflammation, Regeneration, and Therapeutic Innovation

Macrophages play pivotal roles in tissue repair through remarkable functional plasticity, orchestrated by their developmental origins and local microenvironmental cues. Embryonically derived resident macrophages primarily maintain tissue homeostasis, while monocyte-derived macrophages respond predominantly to inflammation and extracellular matrix remodeling. Effective tissue repair requires precise temporal regulation of macrophage polarization, balancing inflammation resolution, angiogenesis, and scar formation. Metabolic reprogramming further enhances macrophage plasticity, enabling adaptation to fluctuating energy demands at injury sites. Emerging evidence also highlights that macrophages integrate biomechanical forces-such as matrix stiffness and shear stress-with biochemical signals to fine-tune their inflammatory and reparative programs. Recognizing this mechanoregulation broadens therapeutic avenues for precisely modulating macrophage behavior in regenerative medicine. Targeting macrophage subsets, polarization states, or metabolic pathways has emerged as a promising therapeutic strategy to optimize healing outcomes. However, the inherent complexity of macrophage heterogeneity presents considerable challenges to therapeutic precision. This review systematically summarizes the multifaceted roles of macrophages in tissue repair, emphasizing how developmental origins dictate functional specificity, dynamic phenotypic transitions, and metabolic adaptability, aiming to advance macrophage-based precision therapeutics for regenerative medicine.