Comprehensive molecular analysis of uveal melanoma identifies targets in tumor-intrinsic and tumor-extrinsic pathways.

In uveal melanoma (UM), the most common primary intraocular tumor, up to half of patients develop fatal metastases despite high local tumor control. Effective treatments for genetically high-risk tumors remain limited, largely due to challenges posed by cancer stem cells (CSCs) and the tumor microenvironment (TME), which sustain tumor progression and resistance. Our study evaluated stemness properties in UM tumor cells, focusing on STAT3 and ANGPTL4, markers linked to cancer aggressiveness and stem-like niches. Using patient samples, we analyzed the TME and CSCs via immune microarrays, RNA in situ hybridization, immunohistochemistry, and bioinformatics, generating comprehensive expression profiles. TNFRSF14 and IKBKE were identified as biomarkers of disease severity. In high-risk BRCA1-associated protein 1 (BAP1)-negative tumors, T cell function and tumor necrosis factor (TNF) superfamily genes were downregulated, indicating immune evasion. These findings underscore ANGPTL4, STAT3, and TNFRSF14 as potential biomarkers and drug targets, emphasizing the need to address tumor-intrinsic and tumor-extrinsic pathways to improve treatment strategies.