The microbiome in head and neck squamous cell carcinoma: Biological drivers, therapeutic interactions, and emerging clinical applications

Head and neck squamous cell carcinoma (HNSCC) develops within a biologically complex niche shaped by epithelial, immune, environmental, and microbial interactions. Growing evidence indicates that microbial communities influence HNSCC initiation, progression, therapeutic response, and toxicity. This narrative review synthesizes current knowledge on microbiome composition in healthy mucosa, oral potentially malignant disorders, and established HNSCC, emphasizing how dysbiosis characterized by enrichment of periodontitisassociated taxa such as Fusobacterium and Porphyromonas and depletion of protective genera including Corynebacterium and Kingella may drive carcinogenesis through inflammation, genotoxic metabolites, immune modulation, and metabolic alterations. We also examine microbiome-mediated effects on systemic treatments, including chemotherapy, radiotherapy-induced mucositis, and immune checkpoint inhibitor (ICI) response, and review emerging approaches to therapeutically modulate microbial communities. Although several microbial signatures show potential as biomarkers or therapeutic targets, no reproducible microbiome-based tools are yet ready for clinical implementation. Standardized methodologies and prospective interventional studies will be essential to translate these findings into precision oncology for HNSCC.