Targeting Tumor‑Associated Macrophages in Osteosarcoma: From Molecular Reprogramming to Immuno-Regenerative Scaffolds

The clinical prognosis for osteosarcoma (OS) remains bottlenecked by chemoresistance and pulmonary metastasis. OS features dense infiltration by tumor‑associated macrophages (TAMs) that are hijacked into an immunosuppressive, pro-tumorigenic M2-like phenotype. Overcoming this therapeutic plateau requires a paradigm shift toward active remodeling of the tumor immune microenvironment. This review evaluates the trajectory of TAM-targeted interventions in OS, emphasizing the critical transition from monotypic phagocytosis checkpoint blockade (e.g., CD47, GD2) to multimodal synergistic regimens. We systematically dissect how next-generation nanomedicine, targeted metabolic stressors (ferroptosis, cuproptosis), and pharmacological rewiring can forcibly induce immunogenic cell death and reverse M2 polarization. Addressing the unique reconstructive demands of OS, we spotlight the development of immuno-regenerative scaffolds—bifunctional biomaterials engineered to synchronize post-resection tumor clearance with active osteogenesis. Finally, we highlight how spatial transcriptomics and biomimetic platforms are mapping physical immune-exclusion barriers and novel therapeutic subpopulations. Breaking the OS therapeutic stalemate ultimately demands interventions that breach these spatial architectures and fundamentally reprogram TAMs, guided by real-time functional imaging (e.g., ferumoxytol MRI) and high-resolution biomarkers (e.g., PSME2).