Macrophage-centered immunotherapy for osteosarcoma: mechanisms, repolarization, and translational strategies.

Despite multimodal treatment strategies, survival rates for osteosarcoma have remained stagnant, and immune checkpoint blockade targeting PD-1/PD-L1 alone has demonstrated limited clinical benefit. Tumor-associated macrophages (TAMs), which are abundant in osteosarcoma and predominantly exhibit an M2-like polarization, contribute significantly to immunosuppression, angiogenesis, metastasis, and chemotherapy resistance. This review outlines the origins and polarization dynamics of TAMs, and highlights central mechanisms through which they impair T-cell function (e.g., PD-1/PD-L1, TIM-3/galectin-9), inhibit phagocytosis (CD47/SIRPα), facilitate metastatic spread (CCL18–Wnt/β-catenin, COX-2/STAT3), and promote therapy resistance (IL-1β, extracellular vesicles). Emerging therapeutic strategies include depleting TAMs or inhibiting their recruitment (via CCL2/CCR2 or CSF1R blockade), disrupting checkpoint signals (anti-CD47/SIRPα, PD-1/PD-L1 inhibitors), and reprogramming M2 TAMs toward an M1 phenotype using pharmacological agents, nanotherapeutics, physical modalities (e.g., R848, photothermal therapy), and metabolic signaling inhibitors (PI3Kγ, ERK5). Innovative approaches such as CAR-macrophages and combined immune–vascular targeting may further amplify antitumor responses. Key challenges, including non-standardized markers, methodological variability, and spatiotemporal heterogeneity, underscore the need for a TAM-reprogramming paradigm over mere depletion, and support the integration of multi-omic spatial profiling and biomarker-driven clinical trials focused on metastatic disease. Ultimately, macrophage-targeted therapies integrated with conventional treatments hold promise for improving outcomes in osteosarcoma.