Aberrant expression of transcription factors (TFs) is a key mechanism mediating tumor immune escape and therapeutic resistance. The involvement of E26 transformation-specific (ETS) family of TFs in immune regulation is not fully understood. The study aimed to elucidate the function of E-twenty-six variant 4 (ETV4) in tumor immune evasion and its potential as a predictive biomarker for immunotherapy in melanoma.

The expression patterns of ETS family TFs were analyzed in melanoma and hepatocellular carcinoma (HCC). Single-cell RNA sequencing (scRNA-seq) was used to dissect the cellular expression and function of ETV4 in the tumor microenvironment. Functional studies and murine models were employed to investigate the role of ETV4 in T cell-mediated tumor killing and tumor growth. The correlation between ETV4 expression level and patient responsiveness to programmed cell death protein 1 (PD-1) blockade therapy was evaluated.

TFs in the ETS family were found to effectively stratify melanoma and HCC patients into prognostic subgroups. In melanoma, the polyoma enhancer activator 3 (PEA3) subfamily, particularly ETV4 and ETV5, showed a negative correlation with immune infiltration. scRNA-seq analysis showed that ETV4 is preferentially expressed in melanoma cells and involves in mediating tumor-immunocyte interactions. Functional studies demonstrated that ETV4 impairs T cell-mediated tumor killing by transcriptionally upregulating programmed death-ligand 1 (PD-L1). In immunocompetent murine models, ETV4 downregulation significantly suppressed tumor growth. Furthermore, high ETV4 expression correlated with poor responses to anti-PD-1 therapy.

Our findings identify ETV4 as a key transcriptional regulator of immune evasion in melanoma by controlling PD-L1 expression. ETV4 may act as a predictive biomarker for immunotherapy outcomes.