Research on prognostic markers and targeted therapy for oral squamous cell carcinoma based on immunogenic cell death

Background Immunotherapy targets for oral squamous cell carcinoma (OSCC) are scarce. Immunogenic cell death (ICD) mediated anti-tumor immunity provides a new direction for prognosis evaluation and treatment of OSCC, but the related core markers and targeting strategies are not clear. Objectives This study aims to systematically identify ICD-related core prognostic markers for OSCC, construct an effective prognostic risk model, and explore potential targeted immunotherapy strategies against these core markers. Methods In this study, the OSCC transcriptome and single-cell sequencing data of TCGA and GEO databases were integrated. ssGSEA and WGCNA were used to screen the differentially expressed genes related to ICD, and Cox regression was used to construct a prognostic model. The expression characteristics of core genes were verified by single-cell analysis and immunohistochemistry. Drug candidates were screened by DGIdb drug prediction and molecular docking. In vitro cell experiments were performed to verify its regulatory effect on CD8 + T cell-mediated anti-tumor immunity. Results CTLA4, TNFRSF4, and CD5 were selected as core prognostic genes according to the hazard ratio (HR) < 0.7 and the genes with excessive confidence intervals were removed. The risk model constructed in this study could stratify OSCC patients into distinct prognostic groups, with area under the curve (AUC) values for 1-, 2-, and 3-year overall survival reaching 0.625, 0.600, and 0.604 in the training set, and 0.673, 0.667, and 0.661 in the validation set. The TNFRSF4 expression signal was concentrated in T cell clusters. The small molecule Compound 1 was predicted as a potential drug to target TNFRSF4, and the binding energy of TNFRSF4 was -9.6 kcal/mol. TNFRSF4 protein expression was upregulated in CD8 + T cells co-cultured with OSCC cells after C1 treatment ( P < 0.05). Compound 1 could activate CD8 + T cells, enhancing tumor-killing activity and inducing apoptosis of OSCC cells ( P < 0.05). Conclusion CTLA4, TNFRSF4, and CD5 can be used as prognostic markers of OSCC, and TNFRSF4 is a potential immunotherapy target. Compound 1 may activate CD8 + T cell-mediated anti-tumor immunity by targeting TNFRSF4, which provides a new strategy for the immunosensitization therapy of OSCC.