Immunometabolism of macrophages in the bone microenvironment: a new perspective for bone healing therapy

This review addresses five core concepts. First, it delineates the spatiotemporal roles and phenotypic shifts of macrophages in the different phases of bone healing. Second, it explores how the reprogrammed metabolism of glucose, lipids, and amino acids underlies macrophage polarization and function. Third, it emphasizes how microenvironmental cues, including cytokines, metabolic intermediates, and microbiota-derived metabolites, modulate macrophage immunometabolism. Fourth, it summarizes emerging therapeutic strategies designed to regulate macrophage metabolism for bone regeneration, such as cell-based therapies, immunomodulatory hydrogels, and nanotechnologies. Finally, it identifies major challenges in this field. These include the temporal-spatial complexity of immunometabolism, the lack of human-relevant models, the emerging concepts of cross-system regulation, and the technological limitations in targeted regulation. Together, these insights provide a conceptual basis for future precision immunometabolic interventions in bone repair.