Background <p>Head and neck squamous cell carcinoma (HNSCC) exhibits marked heterogeneity driven by both tumor-intrinsic programs and immune context. However, the relationship between epithelial proliferation and immune activity remains incompletely defined.</p> Methods <p>We combined bulk transcriptomic analyses of HNSCC cohorts (GSE83519 and TCGA-HNSC) with single-cell RNA sequencing data derived from OSCC (GSE172577) to identify gene programs associated with tumor progression. Co-expression network analysis was used to identify tumor-related modules, and candidate genes were evaluated by survival analysis and experimental validation. Single-cell analysis of an OSCC cohort and CopyKAT-based epithelial cell identification were performed to define cell-type-specific expression patterns.</p> Results <p>EOMES and SPRYD3 were identified as candidate prognostic markers associated with distinct biological programs. Single-cell analysis showed that SPRYD3 expression was enriched in aneuploid epithelial cells, whereas EOMES expression was restricted to cytotoxic lymphocyte populations. Tumor epithelial cells with high SPRYD3 expression exhibited activation of cell cycle and DNA replication pathways, while immune-related signaling was reduced. In contrast, EOMES expression was associated with interferon response and T-cell effector programs. Experimental validation supported increased SPRYD3 expression, whereas EOMES exhibited a tendency toward lower expression in OSCC tissues.</p> Conclusions <p>SPRYD3 and EOMES represent distinct transcriptional programs associated with epithelial proliferation and immune activity in HNSCC. These findings provide a framework for understanding tumor–immune interactions and highlight the potential prognostic and biological relevance of EOMES and SPRYD3 in HNSCC.</p>