Upregulated E26 Transformation-Specific Variant Transcription Factor 7 in Oral Squamous Cell Carcinoma: Clinicopathological Correlations and Immune Regulatory Mechanisms.

Background: E26 transformation-specific variant transcription factor 7 (ETV7) is implicated in various cancers, but its role in oral squamous cell carcinoma (OSCC) remains undefined. This study explores the clinicopathological significance and molecular mechanisms of ETV7 upregulation in OSCC.

Methods: ETV7 protein expression was assessed via immunohistochemistry (IHC) in 173 OSCC and 60 non-OSCC tissues. ETV7 mRNA levels were analyzed using bulk RNA sequencing and single-cell RNA sequencing, supplemented by immune infiltration, enrichment and cell communication analysis.

Results: IHC revealed significantly higher ETV7 protein expression in OSCC than in non-OSCC tissues (P < 0.001), correlating with advanced T (r = 0.380, P < 0.001) and N stages (r = 0.592, P < 0.001). High-throughput data confirmed ETV7 mRNA upregulation (standardized mean difference (SMD) = 0.35, 95% confidence interval (CI): 0.15 - 0.56; summary receiver operating characteristic (s receiver operating characteristic) area under the curve (AUC) = 0.78, 95% CI: 0.74 - 0.81), with levels decreasing twofold post-nivolumab treatment (P < 0.001). Enrichment analysis pinpointed the immune response-regulating signaling pathway as a key mechanism, supported by elevated immune cell infiltration (e.g., CD8⁺ T cells) in high-ETV7 samples. SLC15A4 and DAB2IP emerged as potentially overexpressed ETV7 targets. Cell communication analysis showed ETV7 enhancing myeloid cell interactions via the midkine (MK) pathway.

Conclusions: ETV7 upregulation drives OSCC progression, potentially through immune microenvironment modulation, positioning it as a candidate biomarker and therapeutic target. Its association with clinical stage and immunotherapy response underscores its prognostic relevance in OSCC management.