E26 transformation-specific translocation variant 4 participates in melanoma progression and immune evasion by mediating the CD47molecule/signal regulatory protein α pathway

Melanoma is an aggressive form of skin cancer with few effective treatments available at advanced stages. E26 transformation-specific translocation variant 4 (ETV4) is implicated in tumor progression in several malignancies. However, its role in melanoma and immune evasion remains poorly defined. The objective of this study was to investigate the expression and function of ETV4 in melanoma. ETV4 expression in melanoma tissues and cells was assessed by bioinformatics, quantitative PCR, Western blotting, and immunohistochemistry. Melanoma cell lines with ETV4 overexpression or knockdown were assessed for colony formation, wound healing, and Transwell migration/invasion. The regulatory relationship between ETV4 and integrin-associated protein (CD47) was investigated via dual-luciferase reporter assays and chromatin immunoprecipitation. Macrophage-mediated phagocytic activity was assessed using flow cytometry. ETV4 was markedly upregulated in melanoma tissues and cells, correlating with poor patient survival. Overexpression of ETV4 facilitates melanoma cell proliferation, migration, and invasion. Mechanistically, ETV4 directly bound to the CD47 promoter, transcriptionally activating its expression. ETV4 overexpression enhanced the phosphorylation of Src homology region 2 domain-containing phosphatase-1 and suppressed macrophage phagocytosis, suggesting activation of the CD47/signal regulatory protein α immune checkpoint pathway. Notably, knockdown of CD47 reversed the immunosuppressive effects induced by ETV4 overexpression, restoring macrophage phagocytic activity. ETV4 promotes melanoma progression and immune evasion by upregulating CD47 and activating the CD47/signal regulatory protein α signaling axis. Targeting the ETV4/CD47 pathway may represent a promising therapeutic option to enhance antitumor immunity in melanoma.