Oral Dysbiosis, Immune Dysregulation, and Systemic Oncogenesis

The oral cavity is known for having one of the most diverse and densely populated microbial ecosystems in the human body. Under physiological conditions, this microbial community exists in a state of symbiosis with the host, supported by salivary proteins, epithelial barriers, and a calibrated local immune responses. Nevertheless, disruptions in this ecosystem caused by poor oral hygiene, diet, smoking, or systemic disease can alter the equilibrium and result in dysbiosis. Dysbiosis is characterized by the overgrowth of proteolytic, pro-inflammatory pathobiodonts such as Porphyromonas gingivalis, Fusobacterium nucleatum, Treponema denticola, Candida albicans, and oncogenic viruses including Herpesvirus (HSV) and Human Papillomavirus (HPV), accompanied by the loss of commensal protective species and a reshaped oral immune landscape. This shift converts homeostatic tolerance into chronic, low-grade inflammation, disrupts epithelial and barrier integrity, and drives the release of microbial products (for example, hydrogen sulfide, LPS, and 16S rRNA) and inflammatory mediators into the systemic circulation, thereby reprogramming innate and adaptive immune responses at distant sites. Emerging evidence supports a causal role for oral pathobionts in cancer initiation and progression. A recent study has shown that patients who had higher levels of the red and orange complex periodontal microorganisms (such as Porphyromonas gingivalis, Prevotela intermedia, and Fusobacterium nucleatum), and Candida albicans had an increase in 3.5-fold in risk for developing pancreatic cancer (Meng et al., 2025). Consistent with this, microbial DNA and intact bacterial components from oral taxa, including F. nucleatum and Prevotella intermedia, have been detected within distant tumors such as metastatic brain lesions, indicating systemic dissemination and tissue colonization. In preclinical models, F. nucleatum promotes colorectal tumor growth through activation of Wnt/β-catenin signaling and induction of pro-inflammatory cytokines, establishing a direct link between microbial colonization and oncogenic pathway activation. In parallel, microbial metabolites such as hydrogen sulfide can induce autophagy and survival pathways in host cells, further supporting tumor persistence. Together, these findings point to a mechanistic framework in which oral microorganisms actively shape tumor biology at local and distant sites.Current evidence converges on three mechanistic routes through which oral dysbiosis can influence tumor biology: (1) direct translocation of oral pathobionts to distant tissues, where they colonize tumor environments and deliver oncogenic virulence factors; (2) systemic immune modulation, including sustained low-grade endotoxemia, chronic inflammation, and reprogramming of innate and adaptative responses; and (3) metabolic signaling, whereby oral microbial metabolites enter the circulation and reshape distant tissue niches. Advances in gnotobiotic models, shotgun metagenomics, and immune profiling have begun to define these pathways. However, key gaps remain in n establishing causality and in resolving how these mechanisms interact across tissues and disease stages. This Research Topic aims to advance the field of oral microbiome-oncology by bringing together original research, reviews, and perspectives that define how oral dysbiosis drives oncogenesis beyond the oral cavity, with emphasis on causal immunological and molecular mechanisms. The objectives are to define the microbial shifts that establish pro-oncogenic dysbiosis, delineate the immune pathways linking oral inflammation to distant tumor microenvironments, and test whether correcting dysbiosis reduces cancer risk and improve responses to immunotherapy. To advance causal understanding of how oral dysbiosis drives systemic oncogenesis, we welcome articles addressing, but not limited to, the following themes:• Microbial and functional signatures that define pro-oncogenic oral dysbiosis associated with increased cancer risk at extraoral sites• Mechanistic pathways of oral pathobiont dissemination and colonization of distant tumor sites (colorectal, pancreatic, liver, breast)• Immune mediators linking oral dysbiosis to systemic oncogenesis, including T cell regulation, pro-inflammatory cytokines, and immunomethabolic reprogramming• Oral-gut, oral-pancreas, and oral-colorectal axes: microbial, immunological, and metabolic crosstalk• Salivary microbial and immune biomarkers for early detection and risk stratification of dysbiosis-associated cancers• Preclinical models (animal, organoid, multi-tissue chips) that establish causal links between oral dysbiosis and tumor initiation or progression• Interventional studies testing whether modulation of oral dysbiosis (periodontal therapy, probiotics, prebiotics, targeted antimicrobials) alters systemic immunity and tumor burden• Epidemiological and longitudinal studies defining oral dysbiosis as a modifiable risk factor for extraoral malignancies• Tools and technologies to monitor cancer risk and optimize detection and therapy in response to oral microbiome modulation.We welcome studies that define the reciprocal interactions between oral microorganisms and distant organs, with a focus on mechanistic, basic, and translational insights into how oral dysbiosis drives systemic cancer development. Topic editors: Cristiane Miranda Franca, Nadya Lumelsky, Mauricio Gonçalves Da Costa Sousa Source: https://www.frontiersin.org/research-topics/81511/oral-dysbiosis-immune-dysregulation-and-systemic-oncogenesis