Causal mediation of immune cells in autoimmune liver diseases and oral cancer risk: a mendelian randomization study

Background: Emerging evidence suggests shared immune pathways between autoimmune liver diseases (AILDs) and oral cavity cancer (OCC), yet their causal interdependence remains poorly characterized. Methods: This study employs bidirectional Mendelian randomization (MR) with mediation analysis to systematically investigate the immunological interplay, particularly focusing on CD8 + T cell activity as potential mediator. Results: Genetically predicted PSC increased OCC risk (IVW OR = 1.00016, 95% CI: 1.00004–1.00028, p = 0.009); individuals in the top polygenic risk score (PRS) decile exhibited a 0.1% elevated OCC risk per 1-SD increase (OR = 1.001, 95% CI:1.0002–1.0020). After expanding OCC sample size (1,135 cases), PSC conferred higher OCC risk (OR = 1.1200, 95% CI:1.0100–1.2400, p = 0.029). PSC elevated CD8 + T cell absolute count (CD8 + T-cell AC) (OR = 1.05977–1.06767, p <0.001). After expanding the sample size of OCC (1135 cases), the risk of PSC and OCC was 1.12 (95% CI: 1.01-1.24, p = 0.0290). CD8 + T-cell AC mediated 12.47% of PSC’s total effect on OCC (β = 0.01412, 95% CI: 0.0006–0.0276, p = 0.0401). No causal effects were observed for PBC, AIH, or reverse pathways. Conclusions: This study provides the first genetic evidence establishing PSC as a causal risk factor for OCC via immune cell mediation, offering translational potential for enhanced surveillance, early detection protocols, and targeted immunotherapies in high-risk AILD patients.