Exosomal CircRNA_102619–miR-330-3p Interaction Regulates Osteosarcoma Progression and Metastasis by Forming the Lung Pre-Metastatic Niche

Osteosarcoma, the most prevalent primary bone tumor, predominantly influences children and adolescents. The pre-metastatic niche (PMN) is a specialized microenvironment that forms before clinically detectable metastatic lesions. Cancer-associated fibroblasts (CAFs) play a crucial function in triggering lung metastasis by coordinating PMN formation in the lung. We found that circRNA_102619, delivered by osteosarcoma-derived extracellular vesicles (EVs), promotes the reprogramming of lung fibroblasts (LFs) into CAFs and PMN formation both in vitro and in vivo. High-throughput protein array analysis revealed that CXCL10, a critical factor secreted by CAFs, drives osteosarcoma proliferation, migration, and resistance to natural killer (NK) cell cytotoxicity. Additionally, circRNA_102619 acts as a sponge for miR-330-3p, thereby controlling CXCL10 production. Importantly, in vivo studies confirmed that osteosarcoma-derived EVs enhance lung PMN formation, promoting osteosarcoma progression and metastasis. Inhibiting osteosarcoma-derived EVs represents a novel strategy to block osteosarcoma progression and metastasis.