Tumor microenvironment in bone sarcomas: Implications for immunotherapy and emerging therapeutic vulnerabilities (Review)

Bone sarcomas remain lethal despite multimodal therapy, primarily because the mineralized, immunosuppressive tumor microenvironment (TME) promotes chemo-and immune-resistance.Integrating single-cell and spatial omics across osteosarcoma, Ewing sarcoma and chondrosarcoma delineates subtype-specific TME archetypes dominated by M2 macrophages, exhausted T cells and a stiff extracellular matrix.Mechanistic dissection reveals tractable vulnerabilities, myeloid reprogramming, extracellular matrix modulation and metabolic and epigenetic checkpoints, that can be targeted with bone-selective delivery systems and biomarker-driven combination trials to convert therapeutic failure into durable remission.Therefore, the aim of the present review is to synthesize the latest single-cell, spatial and functional data to map bone-sarcoma TME heterogeneity, dissect resistance mechanisms and propose integrated, biomarker-guided therapeutic strategies that can be translated into treatments. Contents1. Introduction 2. Deconstructing the bone sarcoma TME: Cellular and non-cellular 3. Mechanisms of immunosuppression within the bone sarcoma TME 4. Immunotherapy in bone sarcomas: Current landscape and TME-driven challenges 5. Therapeutic targeting of the bone sarcoma TME 6. Preclinical models and emerging technologies 7. Future directions and translational challenges 8. Conclusion