Systems analysis of the HPV-microbiome-biofilm triad.

Background: Human papillomavirus (HPV) remains the leading cause of cervical cancer worldwide, however, its pathogenesis cannot be sufficiently explained by viral factors alone. Accumulating evidence highlights the critical role of cervicovaginal microbiome composition and biofilm formation in shaping viral persistence, epithelial barrier disruption and carcinogenic progression. Methods: This systems-based integrative synthesis analyzed peer-reviewed literature published between January 2000 and July 2025, retrieved from PubMed and Google Scholar with additional records identified through backward citation screening. The collected data were synthesized to construct a conceptual model of the HPV-microbiome-biofilm triad and to evaluate its clinical and biological implications. Results: The analysis indicates that depletion of Lactobacillus-dominated communities and expansion of anaerobic taxa, particularly Gardnerella vaginalis, are associated with biofilm development, chronic inflammation and immune modulation. These interrelated processes form self-reinforcing feedback loops that promote HPV persistence and reduce therapeutic efficacy. Microbiome dysbiosis and biofilm formation were further linked to impaired epithelial integrity, altered cytokine signaling pathways and clinically relevant phenotypes including immune escape, metabolic shifts and treatment non-responsiveness. Discussion: This systems perspective challenges reductionist pathogen-centered models and emphasizes the importance of integrating microbiome profiling and biofilm dynamics into cervical cancer risk stratification and therapeutic strategies. The coupled interactions between microbial communities, host immunity and viral persistence underscore the cervicovaginal ecosystem as an active regulator of disease progression rather than a passive bystander. Incorporating ecosystem-based parameters into clinical decision-making may enhance prognostic assessment and improve treatment outcomes, particularly in low- and middle-income countries where high HPV prevalence coincides with increased microbiome vulnerability. Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/, identifier CRD420251208178.