Metabolic Regulation of Macrophages in Health and Disease

Abstract

Macrophages orchestrate immune responses through remarkable phenotypic plasticity, which is intrinsically linked to their ability to reprogram intracellular metabolic pathways in response to microenvironmental cues. While recent advances have highlighted the role of aberrant macrophage metabolism in diverse diseases, a systematic synthesis integrating both intracellular and extracellular metabolic signals remains lacking. This review provides a comprehensive framework for understanding how core metabolic pathways—glycolysis, the TCA cycle, oxidative phosphorylation (OXPHOS), fatty acid oxidation (FAO), and amino acid metabolism—are rewired during macrophage polarization under the orchestration of upstream signaling cascades, including NF‐κB, PI3K/AKT/mTOR, JAK–STAT, and MAPK. We examine how exogenous metabolites such as succinate, itaconate, lactate, and amino acids reciprocally regulate macrophage function and discuss tissue‐specific metabolic signatures of macrophage subsets—including alveolar macrophages （AMs), Kupffer cells (KCs), and tumor‐associated macrophages (TAMs)—in the context of obesity, Type 2 diabetes (T2D), metabolic dysfunction‐associated steatotic liver disease (MASLD), infections, autoimmune disorders, and cancer. We further evaluate emerging therapeutic strategies targeting macrophage metabolism, summarizing preclinical and clinical advances across signaling pathways, metabolic nodes, cytokines, and cell‐based therapies with detailed trial data. By integrating cell‐intrinsic metabolic circuitry with extracellular signals, this review establishes a theoretical foundation for metabolism‐targeted immunotherapies and identifies key knowledge gaps for future investigation.