Abstract
Osteosarcoma, the most aggressive primary malignant bone tumor, has stagnant therapeutic outcomes despite decades of standard MAP chemotherapy and surgery; 5-year overall survival (OS) is <30% for metastatic/recurrent cases. Plagued by genomic heterogeneity, immunosuppressive TME, and low immunogenicity, emerging immunotherapies lack robust large-scale clinical validation. We systematically analyzed 864 interventional osteosarcoma trials from Trialtrove (as of September 2025). Results showed trial numbers peaked at 54 in 2021, with 77.3% past (completed/terminated) and over 94% in phase I/II (only 3.6% phase III-IV). Geographically, the U.S. dominated (60.9%, focusing on immunotherapy/targeted therapy), while low- and middle-income countries (LMICs) accounted for <2% of trials despite bearing 40% of the global disease burden. Conventional chemotherapy remains the cornerstone, with immuno-oncology (540 trials) as the leading novel strategy; top targets include VEGFR2 (104), PD-1 (70), and mTOR (60). Biomarker use was imbalanced: liver/nutritional markers prevailed, while key immune/genomic biomarkers (CD8A, TP53) were underrepresented (<8% combined). Key challenges include severe trial-phase imbalance, global disparities, and preclinical-clinical gaps; opportunities lie in synergistic novel therapies (ICI combinations, GD2-targeted CAR-T) and decentralized clinical trials (DCT). Future priorities: accelerate late-phase trials for promising regimens, reduce global disparities via regional consortia, integrate precision biomarkers for patient stratification, and translate TME insights into trials. This analysis highlights the need to shift from conventional chemotherapy optimization to precision-driven, globally equitable strategies to improve outcomes for high-risk osteosarcoma patients.