BACKGROUND: Extensive tumor cell metastasis is associated with poor patient prognosis. Tumor endothelial cells demonstrate distinct proangiogenic phenotypes compared to normal endothelial cells, partially mediated by pericyte-derived secreted factors. Endosialin, a pericyte biomarker implicated in vascular maturation and metastatic progression, remains mechanistically undefined in this context. METHODS: B16F10 melanoma cells were injected via caudal vein into Endosialin knockout (EN) and wildtype mice. Lung metastases were quantified through hematoxylin-eosin (HE) staining. Vascular architecture was analyzed using Evans blue perfusion and CD31 immunofluorescence. Molecular mechanisms were investigated through western blotting, qPCR, proliferation assays, and lumen formation models. RESULTS: Bioinformatics analysis revealed Endosialin overexpression correlates with enhanced angiogenesis and poor clinical outcomes. Endosialin deficiency significantly reduced pulmonary metastasis burden. Vascular profiling showed EN mice exhibited increased small-diameter vessels (<50 μm) and reduced mature vessels (≥50 μm). Mechanistically, Endosialin regulates vascular maturation through Erk1/2-mediated suppression of Cyr61 in pericytes. CONCLUSION: Endosialin facilitates melanoma metastasis by promoting vascular maturation via Erk1/2-Cyr61 signaling axis in pericytes.