Fusobacterium nucleatum in oral squamous cell carcinoma: molecular mechanisms, tumor microenvironment and translational implications.

Fusobacterium nucleatum has increasingly emerged as a microorganism of major interest in microbial dysbiosis-associated carcinogenesis, particularly in oral squamous cell carcinoma (OSCC), where chronic inflammatory remodeling, immune dysfunction, and epithelial plasticity contribute to aggressive tumor behavior and poor clinical outcomes. Recent experimental findings suggests that F. nucleatum may participate in multiple biologic processes linked to OSCC progression, including activation of inflammatory signaling pathways, disruption of epithelial integrity, metabolic adaptation, immune checkpoint-associated suppression, and resistance-related phenotypes. In this review, we critically evaluate current evidence regarding the molecular and cellular interactions of F. nucleatum within the OSCC tumor microenvironment, with particular emphasis on FadA- and Fap2-associated signaling, β-catenin-, NF-κB-, and STAT3-mediated pathways, epithelial-mesenchymal transition (EMT), stromal remodeling, and immune exhaustion signatures. We additionally examine the growing application of spatial transcriptomics, single-cell sequencing, and integrated multi-omics approaches for host-microbe characterization in OSCC. Importantly, current findings remain heterogeneous and context-dependent, varying according to tumor site, HPV status, microbial burden, host immune composition, and methodological variability across studies. Although microbiome-informed biomarkers and therapeutic strategies are increasingly being explored, most remain at early experimental stages and require robust OSCC-specific mechanistic and clinical validation before translational implementation.