Abstract
BACKGROUND: Oral squamous cell carcinoma (OSCC) is associated with poor clinical outcomes and the immune status of its tumour microenvironment (TME) plays a critical role in shaping prognosis. Transcriptomic profiling has become a powerful tool for dissecting immune heterogeneity and identifying key regulatory molecules in OSCC. As central mediators of antigen presentation and antitumor immune activation, major histocompatibility complex (MHC) molecules are essential components of the immune response; however, the prognostic value and regulatory mechanisms of MHC-related genes in OSCC remain insufficiently defined. METHODS: OSCC transcriptomic data from TCGA and GEO were integrated to construct a prognostic RiskScore using differential expression and Cox analysis. Immune infiltration was assessed with ESTIMATE. Immunohistochemistry and immunofluorescence were performed on clinical OSCC tissues to evaluate the relationship between granzyme B (GZMB) and CD8⁺ T cells. A C3H tumour-bearing mouse model with intratumoral IFN-γ injection was used to validate the effects of IFN-γ on tumour growth, immune infiltration and GZMB expression. RESULTS: An eight-gene MHC-related RiskScore was identified as an independent prognostic factor for OSCC. GZMB was highlighted as a key gene, highly expressed in early-stage OSCC and strongly correlated with activated CD8⁺ T cells, but reduced in advanced disease. IFN-γ administration in vivo inhibited tumour growth, increased Cd3⁺ T-cell infiltration and enhanced IFN-γ and GZMB co-expression within necrotic regions. CONCLUSION: This study established a robust prognostic model for OSCC based on MHC-related genes and demonstrated that IFN-γ enhances antitumor immunity through GZMB-mediated cytotoxic activation. The IFN-γ-GZMB axis appears to represent a critical regulatory pathway within the OSCC immune microenvironment and provide a promising therapeutic target and mechanistic basis for immunotherapy in OSCC.