Oral Microbiome–Host Genomic Crosstalk in Oral Carcinogenesis—A Narrative Overview of the Literature

Oral squamous cell carcinoma (OSCC) represents a major global health burden, characterized by poor prognosis and limited improvement in survival over recent decades. Increasing evidence indicates that oral carcinogenesis is not solely driven by host genetic alterations but is significantly influenced by the oral microbiome through complex bidirectional interactions. This narrative review synthesizes current knowledge on the crosstalk between oral microbial communities and host genomic instability, with a specific focus on mutation-driven mechanisms. We discuss how microbial dysbiosis contributes to DNA damage, mutational signatures, epigenetic reprogramming, and immune modulation, thereby facilitating malignant transformation. Unlike previous reviews that address microbiome–cancer associations broadly, this work explicitly maps the mechanistic chain from microbial genotoxins through specific DNA repair pathway disruption to mutation accumulation in OSCC, and devotes substantial attention to the underexplored reverse direction—how host immune gene polymorphisms, DNA repair defects, and metabolic reprogramming shape the microbial niche. A comparative analysis with recent high-impact reviews is included. Finally, we outline emerging research directions, including multi-omics integration, single-cell and spatial transcriptomics, microbiome-targeted therapeutics, and artificial intelligence-assisted precision oncology approaches.