Intratumoral microbiota drive immune evasion and disease progression in oral squamous cell carcinoma

Emerging evidence suggests that oral squamous cell carcinoma (OSCC) harbors distinct microbial communities, yet their influence on tumor immunobiology remains unclear. This study investigated the prognostic value of intratumoral microbiota and their role in modulating CD8⁺ T-cell function.

Using TCGA datasets, a 19-microorganism prognostic signature was constructed via Cox and LASSO regression and validated with Kaplan-Meier survival analysis. Comprehensive bioinformatics analyses, including GSEA/GSVA, CIBERSORT, ESTIMATE, pharmacogenomics, and mutational profiling, were performed to explore underlying mechanisms.

The microbial signature demonstrated strong predictive performance, with higher risk scores significantly associated with reduced overall survival (p < 0.001). High-risk tumors exhibited enrichment of PI3K/AKT/mTOR signaling, metabolic reprogramming, and epithelial-mesenchymal transition, alongside an immunosuppressive microenvironment characterized by CD8⁺ T-cell depletion, M0 macrophage infiltration, and upregulation of immunosuppressive markers including CD276 and TGF-β1. Conversely, immune-activating checkpoints such as PD-1 and CTLA-4 were elevated in low-risk tumors. Notably, periodontal pathogens negatively correlated with immune effector activity, and TP53 mutations were more frequent in high-risk cases (82% vs. 67%).

This study identified intratumoral microbial signatures as independent prognostic biomarkers and validated their reproducibility in an external cohort. Our findings support a microbiota-immune axis contributing to immune evasion in OSCC, offering novel avenues for prognostic stratification and therapeutic intervention.