POSTN+ tumor-associated endothelial cells promote and predict pulmonary metastasis in osteosarcoma

Although surgery and chemotherapy have improved survival outcomes for osteosarcoma patients, pulmonary metastasis—whether synchronous or metachronous, remains the leading cause of mortality. This study aimed to elucidate the underlying mechanisms of osteosarcoma pulmonary metastasis and identify specific tumor-associated endothelial cell (TEC) subsets that may contribute to this fatal progression. By integrating single-cell RNA sequencing (scRNA-seq) data, we assessed the microenvironmental heterogeneity between metastatic and non-metastatic osteosarcoma to explore the role of endothelial cells in pulmonary metastasis. These findings were validated through independent scRNA-seq analysis and Western blotting ( n = 4), a real-world clinical cohort ( n = 49), and the TCGA dataset ( n = 91). Furthermore, an integrated multi-omics approach was employed to delineate the mechanistic functions of these TECs in promoting pulmonary metastasis. We identified a novel POSTN⁺ TEC subset critical for driving pulmonary metastasis. Clinical validation confirmed that high POSTN⁺ TEC infiltration serves as an independent predictor of pulmonary metastasis and reduced metastasis-free survival. Mechanistically, POSTN⁺ TECs promote metastasis via dual pathways: POSTN binds to osteoclastic ITGB3, activating FAK-PI3K/AKT signaling to drive bone matrix degradation, while concurrently recruiting and activating Tregs to establish an immunosuppressive niche. POSTN⁺ TECs are key drivers of osteosarcoma pulmonary metastasis, serving as both a robust predictive biomarker and a promising therapeutic target.