Roles of macrophages in tumor immunotherapy: metabolism, immune checkpoints, and combination strategies

Macrophages influence anti-tumor immunity through tractable metabolic and checkpoint programs. Within hypoxic, nutrient-competitive tumor beds, tumor-associated macrophages (TAMs) adopt oxidative and lipid-based metabolisms, dampening antigen presentation and T-cell support. Converging evidence shows that lactate flux, fatty acid oxidation (FAO), and glutamine handling steer TAMs toward immunosuppressive states that blunt checkpoint efficacy. Here, we synthesize the mechanism by which discrete pathways-glycolysis/pentose phosphate pathway (PPP) switching, FAO-lysosomal lipolysis, and glutamine-α-ketoglutarate signaling-mechanistically reprogram TAMs. We then map these circuits onto combination strategies involving programmed cell death (ligand) protein 1/cytotoxic T-lymphocyte antigen-4 (PD-(L)1/CTLA-4) blockade, chemotherapy/radiotherapy, and chimeric antigen receptor T-cell (CAR-T). Rather than providing a catalogue, we emphasize when metabolic rewiring dominates, which TAM subsets are affected, and how these levers can be timed or co-inhibited to restore cytotoxic T-cell function. This approach provides operational guidance for pairing macrophage-directed agents with immune checkpoint inhibitors in solid tumors.