An Exploratory Immune‐Associated Prognostic Signature and AREG‐Associated Phenotypes in Oral Squamous Cell Carcinoma

ABSTRACT Background Oral squamous cell carcinoma (OSCC) remains a clinically heterogeneous malignancy with unsatisfactory long‐term outcomes, particularly in patients with advanced disease and treatment resistance. Conventional clinicopathologic parameters incompletely capture the biological diversity of OSCC and provide limited guidance for individualised therapeutic stratification. Methods We performed an integrated transcriptomic analysis of TCGA‐derived OSCC data to construct and evaluate an immune‐associated prognostic signature. Associations with survival, clinicopathologic features, immune infiltration, somatic mutation profiles and pathway‐level biological programs were assessed. The manuscript‐specified ten‐gene equation was additionally evaluated without refitting in an independent CPTAC oral‐cavity SCC cohort using overall survival, Harrell's C‐index and time‐dependent ROC analysis. Amphiregulin (AREG) was selected for functional investigation using siRNA‐mediated knockdown, proliferation assays, cisplatin sensitivity testing, IC50 estimation and apoptosis analysis in OSCC cells. Results The original TCGA analysis separated survival groups and reported 1‐, 3‐ and 5‐year AUCs of 0.701, 0.693 and 0.623. In 42 independent CPTAC patients with 14 deaths, however, the fixed score was not significantly associated with overall survival (HR per SD, 1.181; 95% CI, 0.674–2.069; p = 0.561). The C‐index was 0.521, and the 1‐ and 3‐year AUCs were 0.369 and 0.550; 5‐year evaluation was unsupported by follow‐up. The supplied AREG experiments suggested reduced proliferation and increased cisplatin sensitivity after knockdown. Conclusions This study identifies an exploratory immune‐associated score and AREG‐associated cellular phenotypes in OSCC.