DNA damage response in bone tumors: mechanisms, therapeutic vulnerabilities, and clinical perspectives

Malignant bone tumors have distinct molecular backgrounds that shape their DNA damage response (DDR) alterations and potential therapeutic vulnerabilities. This review critically examines DDR biology in osteosarcoma (OS), Ewing sarcoma (ES), and chondrosarcoma (CS), distinguishing patient genomic observations, functional studies in tumor models, clinical treatment evidence, and findings extrapolated from other malignancies. OS exhibits extensive structural genomic abnormalities, whereas ES has fusion-associated transcriptional and replication stress. In CS, repair vulnerabilities vary with histological and molecular context. We evaluate how these differences influence proposed DDR dependencies, treatment resistance, and interactions with the tumor microenvironment. Particular attention is given to discrepancies between preclinical sensitivity and clinical outcomes, inconsistent candidate biomarkers, and the limitations of inferring therapeutic dependency from gene expression or genomic instability alone. DDR-targeted combinations and biomarker-guided strategies warrant further investigation, but the available clinical evidence remains limited and heterogeneous. By integrating tumor-specific comparisons with an assessment of functional and clinical validation, this review identifies priorities for translating DDR biology into testable therapeutic strategies.