Metabolic Reprogramming Of Macrophages In Breast Cancer: Mechanisms And Therapeutic Implications

As key immune cells in the tumor microenvironment (TME), macrophages polarize into pro-inflammatory M1 or anti-inflammatory M2 phenotypes, with their functional states tightly linked to metabolic pathway dynamics. This review comprehensively examines macrophage metabolic reprogramming in glycolysis, lipid metabolism, glutamine metabolism, the pentose phosphate pathway (PPP), mitochondrial function, the tricarboxylic acid (TCA) cycle, and amino acid metabolism, while exploring their implications for breast cancer's immune microenvironment and therapeutic approaches. In M1 macrophages, glycolysis is significantly enhanced, promoting the inflammatory response through lactate accumulation and reactive oxygen species (ROS) production. Simultaneously, the TCA cycle is disrupted at the citrate and succinate nodes, leading to the accumulation of metabolic intermediates and further strengthening the pro-inflammatory phenotype. On the other hand, M2 macrophages depend on oxidative phosphorylation (OXPHOS) and fatty acid oxidation (FAO). They regulate epigenetic modifications through metabolites such as alpha-ketoglutarate (α-KG) to maintain anti-inflammatory and tissue repair functions. Breast cancer cells reprogram macrophages via glutamine competition and exosome secretion, driving M2 polarization to support tumor progression. Different molecular subtypes exhibit distinct metabolic features: triple-negative breast cancer (TNBC) shows high glycolytic activity and glutamine addiction, whereas hormone receptor-positive breast cancer relies more on exogenous amino acid uptake. Targeting glycolysis or glutamine metabolism can revert tumor-associated macrophages (TAMs) to an anti-tumor M1-like state, boosting immunity. Although metabolic intervention strategies (such as inhibiting key enzymes hexokinase 2 (HK2), glutaminase (GLS), or fatty Acid Binding Protein 4 (FABP4)) show therapeutic potential, existing studies still have limitations: the compensatory effects between metabolic pathways, tumor heterogeneity, and insufficient clinical translation. Emerging strategies, including metabolic checkpoint targeting, CAR-macrophages (CAR-M), and biomimetic nanocarrier-based delivery systems, hold promise for overcoming these challenges. In summary, in-depth elucidation of the molecular mechanisms underlying macrophage metabolic reprogramming and their metabolic crosstalk with breast cancer cells will provide new insights and novel therapeutic targets for the precise immunometabolic therapy of breast cancer.