The oral microbiota in oral squamous cell carcinoma: unravelling mechanisms and clinical potential

Originating in the mucosal lining of the mouth, oral squamous cell carcinoma is the most common malignancy of the head and neck regions. Its pathogenesis is multifactorial, involving environmental exposures, genetic susceptibility, and lifestyle-related risk factors. Increasing evidence indicates that oral microbial dysbiosis contributes to the initiation and progression of OSCC. Under healthy conditions, the oral cavity harbors a diverse and functionally balanced microbial ecosystem that maintains mucosal integrity, supports immune homeostasis, and prevents colonization by pathogenic species. Disruption of this equilibrium, known as oral dysbiosis, is increasingly recognized as a key event in oral carcinogenesis. In OSCC, a shift toward pathogenic and pro-inflammatory microbial communities has been consistently observed, particularly involving periodontal bacteria such as Porphyromonas gingivalis, Treponema denticola, and Fusobacterium nucleatum. These organisms contribute to tumor progression by activating inflammatory and oncogenic signaling pathways, including NF-κB, STAT3, and PI3K/Akt; suppressing apoptosis; inducing epithelial-mesenchymal transition; and immune evasion, thereby creating a tumor-promoting microenvironment. In addition to bacterial dysbiosis, viral and fungal components of the oral microbiome may act as important cofactors in OSCC. High-risk Epstein-Barr virus (EBV) and human papillomavirus (HPV) have been implicated in disrupting tumor suppressor pathways, causing genomic instability, and modulating the immune response. Fungal species, particularly Candida albicans, may further contribute by producing carcinogenic metabolites and inducing chronic inflammation. This review provides an integrated overview of the oral microbiome in OSCC, focusing on the composition and protective roles of the core microbiota, factors influencing microbial stability, and mechanisms by which dysbiosis contributes to carcinogenesis. It also highlights the oral microbiome as a potential source of non-invasive biomarkers and discusses microbiome-targeted strategies, including prebiotics, probiotics, and postbiotics, as promising adjunctive approaches to restore microbial balance and reduce tumor-promoting inflammation.