From Inflamed Gingiva to Invasive Malignancy: Molecular Crosstalk in Oral Carcinogenesis: A Scoping Review

Oral squamous cell carcinoma (OSCC) develops within a complex inflammatory microenvironment where chronic mucosal inflammation and microbial dysbiosis may contribute to malignant transformation. Increasing evidence suggests that periodontal pathogens associated with chronic gingival inflammation can influence epithelial signaling, immune responses, and tumor progression. This scoping review aimed to map current molecular, genomic, and immunological evidence linking chronic gingival inflammation and periodontal pathogen–associated dysbiosis to OSCC. Following the Population-Concept-Context (PCC) framework, electronic searches were conducted in PubMed, Scopus, and Web of Science through February 2026. Original studies investigating mechanistic links between periodontal inflammation, microbial dysbiosis, and OSCC in human samples, in vitro models, or animal models were included. Data were extracted on microbial drivers, oncogenic signaling pathways, immune modulation, and genomic or epigenetic alterations. A total of 46 studies were included, suggesting that periodontal pathogens, particularly Porphyromonas gingivalis and Fusobacterium nucleatum, may activate oncogenic signaling pathways such as NF-κB, PI3K/Akt, Wnt/β-catenin, and TGF-β. Evidence from in vitro, animal, and human studies indicates that these pathways may contribute to epithelial-mesenchymal transition (EMT), tumor invasion, and resistance to apoptosis. Microbial exposure has also been associated with modulation of the tumor immune microenvironment, including macrophage polarization, suppression of cytotoxic T-cell responses, and enhanced immune checkpoint signaling. In addition, genomic and transcriptomic studies have identified dysregulated genes and microRNAs associated with inflammation-driven carcinogenesis. Overall, chronic gingival inflammation and periodontal dysbiosis appear to contribute to OSCC development through interconnected mechanisms involving inflammatory and cytokine signalling, microbe sensing and innate immune activation, immune suppression and tumor immune escape, EMT, invasion and metastatic signaling, and metabolic reprogramming with regulatory networks. However, as current evidence is largely derived from in vitro and animal studies with limited prospective clinical data, well-designed longitudinal human studies are needed to confirm these associations and support biomarkers discovery and novel preventive or therapeutic strategies targeting early oncogenic events in inflamed oral tissues.