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Oral squamous cell carcinoma (OSCC), representing over 90% of oral cancers and affecting more than 350,000 people worldwide each year, is strongly linked to microbial shifts. Common periodontal pathogens such as Fusobacterium nucleatum and Porphyromonas gingivalis are often enriched in OSCC. These bacteria may promote tumorigenesis by activating NF-\u03baB and STAT3 pathways, suppressing apoptosis, and modulating host immune responses. Additional potential mechanisms include the production of reactive oxygen species (ROS) and genotoxins, inhibition of tumor suppressors such as p53, disruption of cell-cycle regulation via cyclin-dependent kinase pathway, and upregulation of \u03b2-catenin and toll-like receptor signaling. These molecular alterations cause DNA damage, immune surveillance evasion, angiogenesis, promoting tumor progression. Microbiota-modulating therapies, such as Lactobacillus probiotics, may complement standard treatments by restoring balance, boosting immunity, and limiting tumor growth. Engineered bacteriotherapy, microbiome-targeted immunomodulators, and microbiota-based diagnostics expand therapeutic options in oral cancer and, combined with advances in precision medicine, may support more personalized treatments and improved outcomes.<\/jats:p>","DOI":"10.3390\/ijms262010212","type":"journal-article","created":{"date-parts":[[2025,10,21]],"date-time":"2025-10-21T13:42:03Z","timestamp":1761054123000},"page":"10212","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["The Molecular Interplay Between Oral Microbiome and Oral Cancer Pathogenesis"],"prefix":"10.3390","volume":"26","author":[{"given":"Roxana-Nicoleta","family":"Urzic\u0103","sequence":"first","affiliation":[{"name":"Department of Physiology, \u201cCarol Davila\u201d University of Medicine and Pharmacy, 050474 Bucharest, Romania"},{"name":"Department of Oral and Maxillofacial Surgery, \u201cCarol Davila\u201d Central Military Emergency Hospital, 010825 Bucharest, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brigitte","family":"Cre\u021bu","sequence":"additional","affiliation":[{"name":"Department of Oral and Maxillofacial Surgery, \u201cCarol Davila\u201d Central Military Emergency Hospital, 010825 Bucharest, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4200-3069","authenticated-orcid":false,"given":"Ana","family":"C\u0103runtu","sequence":"additional","affiliation":[{"name":"Department of Oral and Maxillofacial Surgery, \u201cCarol Davila\u201d Central Military Emergency Hospital, 010825 Bucharest, Romania"},{"name":"Faculty of Dental Medicine, \u201cTitu Maiorescu\u201d University, 031593 Bucharest, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8787-3829","authenticated-orcid":false,"given":"S\u0103ndica","family":"Bucurica","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, \u201cCarol Davila\u201d University of Medicine and Pharmacy, 050474 Bucharest, Romania"},{"name":"Department of Gastroenterology, University Emergency Central Military Hospital \u201cDr. Carol Davila\u201d, 010825 Bucharest, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4072-038X","authenticated-orcid":false,"given":"Alexandru-Titus","family":"Farcasiu","sequence":"additional","affiliation":[{"name":"Department of Prosthodontics, Faculty of Dentistry, \u201cCarol Davila\u201d University of Medicine and Pharmacy, 37 Dionisie Lupu Street, District 2, 020021 Bucharest, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-5213-1702","authenticated-orcid":false,"given":"Lauren\u021biu Mihai","family":"Ciupescu","sequence":"additional","affiliation":[{"name":"Institute of Hygiene and Veterinary Public Health, 041293 Bucharest, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7676-6393","authenticated-orcid":false,"given":"Cristian","family":"Scheau","sequence":"additional","affiliation":[{"name":"Department of Physiology, \u201cCarol Davila\u201d University of Medicine and Pharmacy, 050474 Bucharest, Romania"},{"name":"Department of Radiology and Medical Imaging, \u201cFoisor\u201d Clinical Hospital of Orthopaedics, Traumatology and Osteoarticular TB, 021382 Bucharest, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4530-7965","authenticated-orcid":false,"given":"Constantin","family":"C\u0103runtu","sequence":"additional","affiliation":[{"name":"Department of Physiology, \u201cCarol Davila\u201d University of Medicine and Pharmacy, 050474 Bucharest, Romania"},{"name":"Department of Dermatology, \u201cProf. N.C. 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