Recent studies have demonstrated that
CD3D
activates T-cell-related signal transduction and is associated with the antitumor immune response in several cancers. This study explored the role of
CD3D
in head and neck squamous cell carcinoma (HNSCC). A total of 499 HNSCC tissues and 44 normal controls were acquired from The Cancer Genome Atlas as the training cohort. GSE65858 included 270 HNSCC patients and was obtained from the Gene Expression Omnibus database as the test cohort. Overall, 172 HNSCC patients were collected as the validation cohort.
CD3D
expression in the validation cohort was measured by quantitative real-time polymerase chain reaction. The Kaplan–Meier plot revealed that high
CD3D
expression was associated with longer overall survival in HNSCC patients. Univariate and multivariate analyses showed that
CD3D
expression was an independent prognostic factor for HNSCC patients, which was confirmed in the test cohort and validation cohort. Furthermore, GO, KEGG, and GSEA analyses revealed the association of
CD3D
with immune-related pathways. Subsequently, ESTIMATE analysis showed the association between
CD3D
and the tumor microenvironment, while ssGSEA showed a remarkable positive link between
CD3D
and immune-related functions. Multiple algorithms demonstrated that high
CD3D
expression was associated with more immune effector cell infiltration. Finally, the tumor immune dysfunction and exclusion (TIDE) score and immunophenoscore (IPS) showed that patients with high
CD3D
could benefit from immunotherapy. In summary,
CD3D
was an independent favorable prognostic biomarker and correlated with immune cell infiltration and immune-related function, as well as an efficient indicator of immunotherapy response for HNSCC patients.