Immunometabolic programming of macrophages and tumor-associated macrophages: metabolic pathways shaping polarization, immune regulation, and disease outcomes

Abstract

Macrophages adapt to hanging tissue environments by rewiring cellular metabolism, and these metabolic programs actively instruct immune functions rather than merely supplying energy. Across health and disease, shifts in glycolysis, mitochondrial oxidative phosphorylation, lipid handling, and amino acid utilization shape macrophage polarization, inflammatory mediator production, antigen presentation, and interactions with lymphocytes. In tumors, these principles are illustrated by tumor-associated macrophages (TAMs), which are reprogrammed by hypoxia, nutrient competition, and tumor-derived metabolites to adopt phenotypes that frequently support immune evasion, angiogenesis, extracellular matrix remodeling, and therapy resistance. This review integrates core macrophage immunometabolic pathways with TAM biology, emphasizing how lactate accumulation, altered lipid mediators, cholesterol remodeling, and amino acid dependencies reshape macrophage states and suppress antitumor immunity through checkpoint signaling and metabolic deprivation. We also discuss how immunometabolism intersects with regulated cell death, highlighting ferroptosis as an emerging mechanism linking iron metabolism, lipid peroxidation, redox control, and immune outcomes. Finally, we summarize therapeutic opportunities targeting metabolic nodes in tumor cells and macrophages, including modulation of lactate transport, fatty acid oxidation and synthesis, arginine/tryptophan pathways, and PI3Kγ-linked programs, and consider how interspecies differences between murine and human macrophages influence translational interpretation. Together, these insights position macrophage immunometabolism as a tractable framework for designing interventions that reshape immune responses in cancer and other macrophage-driven diseases.