Emerging Treatments in Bone Tumors: Lessons Learned from the ESMO Annual Meeting.

Primary bone sarcomas are rare, heterogeneous malignancies with limited therapeutic options, particularly in metastatic disease where outcomes remain poor. This study synthesizes current literature to evaluate emerging therapeutic strategies and biological determinants of response across osteosarcoma, Ewing sarcoma, and chondrosarcoma, as presented at the ESMO Annual Meeting, 2025. Key approaches reviewed include VEGFR-targeted tyrosine kinase inhibitors (TKIs), DNA damage response (DDR) inhibition, MYC targeting, immune checkpoint inhibitors (ICIs), and surfaceome-directed therapies such as antibody-drug conjugates (ADCs) and chimeric antigen receptor T cell therapy. Across studies, TKIs demonstrated short lasting activity as monotherapy but improved outcomes in some of the studies when combined with ICIs or chemotherapy, reflecting their role in remodeling the tumor microenvironment (TME); importantly, controlled studies with TKI and chemotherapy upfront are ongoing. DDR- and MYC-targeted therapies have shown strong preclinical rationale but limited clinical efficacy, highlighting challenges in translation. Immune-based therapies exhibited variable responses, with dedifferentiated chondrosarcoma (DDCS) emerging as a responsive histotype. Surfaceome-targeting strategies, particularly ADCs, demonstrated promising early clinical activity. Overall, bone sarcoma rarity, tumor heterogeneity, immunosuppressive TME, and lack of predictive factors challenge drug discovery for bone sarcoma patients. These findings underscore the importance of combination strategies and biomarker-driven patient selection and suggest that continued integration of targeted and immunotherapeutic approaches will be critical to improving outcomes in bone sarcoma.