TNFSF8 Drives Oral Squamous Cell Carcinoma Progression via CD8+ T Cell Regulation: Insights from Multi-Omics Integration and Single-Cell eQTL Analysis

Background Oral squamous cell carcinoma (OSCC) is a highly aggressive malignancy with limited therapeutic options. This study aimed to investigate the causal role of TNFSF8 in the progression of OSCC through multi-omics integration. Methods Cis-pQTL data from deCODE and the UK Biobank Plasma Proteomics Project (UKB-PPP) were used to perform two-sample Mendelian randomization (MR) analysis to evaluate the association between TNFSF8 and OSCC. Bayesian colocalization was employed to validate causal relationships. Mediation analysis quantified the role of immune cell phenotypes in mediating the TNFSF8-OSCC relationship. Single-cell RNA sequencing (scRNA-seq) was used to analyze the high expression of TNFSF8 in T cells from OSCC tissue.Meanwhile, single-cell eQTL analysis was conducted to further verify the cell-type-specific causal association between TNFSF8 and OSCC. Results MR analysis identified TNFSF8 as a causal factor for OSCC risk. Colocalization analysis confirmed shared causal variants. Mediation analysis revealed that T cell phenotypes significantly mediated the TNFSF8-OSCC relationship. scRNA-seq demonstrated significantly elevated expression of TNFSF8 in T cell subsets from OSCC patients.Single-cell eQTL analysis further found that the expression of TNFSF8 in CD8 + T cells was positively correlated with OSCC risk, reinforcing its cell-type-specific role. Conclusion TNFSF8 drives OSCC progression potentially through the regulation of T cell function. These findings suggest that TNFSF8 is a promising therapeutic target, warranting further validation.