Targeting the metabolic dependencies of tumor-associated macrophages for cancer immunotherapy

Abstract Tumor-associated macrophages (TAMs) play a pivotal role in tumor progression and immune evasion, with recent evidence indicating that metabolic reprogramming is crucial in determining their functional phenotype. Alterations in glucose, amino acid, and lipid metabolism are central to the regulation of TAMs plasticity, driving the shift between pro-inflammatory (M1) and anti-inflammatory (M2) states. M1 macrophages predominantly rely on glycolysis and aerobic metabolism to support their pro-inflammatory functions, while M2 macrophages exhibit enhanced oxidative phosphorylation, which facilitates tissue repair and immune suppression. Given these metabolic distinctions, targeting key metabolic pathways in TAMs presents a promising strategy for reprogramming the tumor microenvironment and enhancing anti-tumor immunity. This review examines the metabolic differences between these distinct macrophage populations, focusing on the regulation of glucose, amino acid, and lipid pathways. Furthermore, we evaluate emerging therapeutic strategies targeting these metabolic pathways aimed at reprogramming TAMs toward an anti-tumor phenotype, enhancing anti-tumor immunity, and overcoming therapeutic resistance. Finally, we discuss the translational progresses and challenges of metabolic interventions, highlighting the potential of targeting macrophage metabolism to convert refractory tumors into immunologically responsive ones and improve the clinical outcomes of cancer immunotherapy.