Emerging Advancements in Metabolic Properties of Macrophages within Disease Microenvironment for Immune Therapy

Background: As sentinel cells of innate immunity, macrophages exhibit microenvironment-driven functional plasticity critical for immune regulation and tissue homeostasis, yet maladaptive metabolic reprogramming-induced polarization dysregulation exacerbates disease progression by manifesting immune dysfunction. Summary: This review systematically deciphers the metabolic signatures governing macrophage polarization – spanning amino acid metabolism, glycolytic flux, lipid dynamics, and iron homeostasis – while dissecting how pathological microenvironments (encompassing tumor niches, atherosclerotic plaques, and obese adipose tissue) co-opt these pathways to drive pathogenesis. Crucially, this analysis demonstrates that cellular metabolism dictates macrophage phenotypic/functional states across disease contexts, with comprehensive decoding of their metabolic networks emerging as imperative for developing next-generation immunotherapies. Key Messages: Therapeutically, pathogenic polarization may be reversed through strategic interventions targeting metabolite-sensing receptors, pharmacologically blocking metabolic checkpoints, and reprogramming core metabolic modalities to restore immunoregulatory competence.