Assessing the current molecular understanding of therapeutic targets in osteosarcoma.

Osteosarcoma, a highly aggressive bone tumor, continues to pose significant treatment challenges despite advances in molecular research. Traditional therapeutic strategies have largely relied on targeting genetic alterations of tumor genes or signaling pathways, but these approaches have been less effective in clinical settings due to the complex biology. Recent insights into the molecular landscape of osteosarcoma have revealed key mechanisms of therapeutic resistance, including tumor plasticity, immune evasion, and metabolic reprogramming. The interaction between the tumor and its microenvironment, such as mechanical stress, hypoxia, and extracellular matrix composition, leads to spatially distinct regions with varying drug sensitivities. We highlight three key shifts in understanding osteosarcoma biology: 'target plasticity' driven by evolving tumor dynamics, the importance of mechanical signaling at the tumor-bone interface, and the potential of multi-omics platforms for real-time monitoring and personalized treatment. We propose a new therapeutic framework that integrates these advances to overcome resistance mechanisms. By focusing on epigenetic reprogramming, immune resetting, and mechanopharmacological approaches, we envision a more comprehensive strategy for osteosarcoma treatment that goes beyond traditional single-target therapies. The success of these strategies will depend on integrating spatially informed, time-resolved treatment regimens, guided by advanced molecular and computational technologies.