Molecular landscape of chondrosarcoma: From tumor biology to therapeutic vulnerabilities

Chondrosarcoma (CS) is the second most common primary malignant bone tumor and comprises a heterogeneous group of cartilage-producing neoplasms with distinct histopathological, molecular, and clinical features. Surgery remains the cornerstone of treatment, whereas intrinsic resistance to conventional chemotherapy and radiotherapy limits therapeutic options for patients with unresectable or metastatic disease. This narrative review critically examines the molecular, genetic, epigenetic, metabolic, and microenvironmental mechanisms underlying CS development, progression, and treatment resistance and evaluates their translational implications. CS subtypes are associated with characteristic molecular alterations, including IDH1/2 mutations in central conventional CS, EXT1/2 disruption in secondary peripheral CS, and HEY1::NCOA2 fusion in mesenchymal CS. Additional alterations involving TP53, CDKN2A/RB1, and the TERT promoter contribute to disease progression. These events interact with dysregulated signaling pathways, metabolic and epigenetic reprogramming, hypoxia, extracellular-matrix remodeling, bone remodeling, and heterogeneous immune states. This biological complexity has prompted the investigation of mutant-IDH inhibitors, death receptor agonists, antiangiogenic and multitarget kinase inhibitors, immune-checkpoint blockade, and therapies targeting cell-cycle, epigenetic, metabolic, and microenvironmental dependencies. Nevertheless, most approaches have produced limited or predominantly cytostatic activity. Ozekibart has provided a positive randomized signal, with improved progression-free survival in conventional CS, whereas mutant-IDH1 inhibitors can achieve durable disease stabilization in selected patients but rarely induce objective responses. Future progress requires subtype-specific trials, assessment of pretreatment tumor growth kinetics, pharmacodynamic confirmation of target inhibition, and prospective integration of genomic, epigenetic, metabolic, and immune biomarkers.