Assessing the current molecular understanding of therapeutic targets in osteosarcoma

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.