Osteosarcoma as a communication-driven disease: redefining tumor-bone signaling networks as therapeutic targets.

Osteosarcoma (OS) is an aggressive primary bone malignancy characterized by high metastatic potential and limited therapeutic progress. Beyond genomic instability, accumulating evidence indicates that OS operates as a communication-driven disease in which dynamic intercellular signaling networks within the tumor microenvironment regulate tumor growth, immune evasion, metastatic dissemination, and therapy resistance. This review integrates current knowledge on immune cell crosstalk, extracellular vesicle-mediated signaling, soluble factors, and direct cell-cell interactions that coordinate local and systemic tumor progression. We discuss how these interconnected communication circuits shape the tumor immune microenvironment and sustain adaptive plasticity. Finally, we highlight emerging strategies aimed at disrupting pathological signaling networks, while acknowledging that many communication-targeted approaches remain at the preclinical stage or require further clinical validation. Framing OS as a communication-driven ecosystem provides a unifying conceptual model to identify novel therapeutic vulnerabilities.