The pivotal role of metabolism in shaping tumor-associated macrophages phenotype and function

Tumor progression is critically shaped by the dynamic interplay between tumor cells and the tumor microenvironment (TME). The TME harbors a diverse array of immune cells, encompassing T cell, B cell, NK cell and macrophages. Among these, TAMs profoundly shape tumor growth and metastasis by interacting with tumor cells and other immune cells. To adapt to the varied immune and metabolic cues in the TME, they undergo dynamic metabolic reprogramming, which recent advances have shown to involve extensive remodeling of glucose, lipid, and amino acid metabolism, along with the tricarboxylic acid cycle. However, critical knowledge gaps remain regarding the cellular heterogeneity of TAM metabolic reprogramming, divergent metabolic signatures across TAM subsets, and context-dependent variations in metabolic rewiring among different cancer types. However, the mechanisms by which these metabolic alterations translate into distinct functional phenotypes and shape the immune landscape of the TME remain poorly defined. This review systematically synthesizes the current knowledge on how metabolic remodeling in TAMs regulates their polarization and pro-tumor functions. We specifically focus on delineating the heterogeneity of TAM metabolic features across tumor types and subsets and discuss the implications of these metabolic variations for TAM-mediated immunosuppression. Furthermore, we summarize the representative therapeutic agents targeting key metabolic nodes in TAMs. By integrating emerging insights into TAM metabolism and associated pharmacologic interventions, this review aims to identify key unanswered questions and provide a theoretical framework for developing precision immunotherapies that target TAM metabolic nodes without compromising anti-tumor immunity.