Therapeutic resistance remains a major obstacle in cancer treatment and limits the durability of immunotherapy, chemotherapy, and targeted therapy. Tumor-associated macrophages (TAMs) contribute to resistance through spatially and functionally heterogeneous programs shaped by hypoxia, vascular niches, metabolic stress, tumor-derived signals, and therapy-induced inflammation. Chronic IFN-γ exposure can also promote adaptive resistance through checkpoint induction, altered antigen presentation, suppressive feedback signaling, metabolic rewiring, and epigenetic remodeling. This review examines how TAM heterogeneity and IFN-γ signaling intersect to support therapy evasion, with emphasis on macrophage niches, phagocytosis resistance, lactate-associated epigenetic regulation, and clinically relevant feedback loops. We also discuss why several TAM-directed strategies, including CSF1R inhibition, have shown stronger activity in preclinical models than in clinical trials. Finally, we evaluate emerging approaches such as macrophage reprogramming, CD47/SIRPα blockade, CAR-macrophage engineering, and biomarker-guided combination therapy. A clearer understanding of TAM states, spatial context, and IFN-γ dynamics may improve patient stratification and support more rational translational strategies to overcome therapeutic resistance.
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