Abstract
Background/Objectives: Persistent high-risk human papillomavirus (HPV) infections are the leading cause of cervical cancer. Developing evidence suggests that the cervicovaginal microbiome plays a significant role in modulating HPV persistence and progression to cervical neoplasia. This review synthesizes the current knowledge on the interplay between the cervicovaginal microbiome and local immunity in HPV infections, emphasizing microbial diversity, immune responses, and potential therapeutic implications. Methods: A thorough review of the literature was performed using Embase, PubMed, Scopus, and Google Scholar, encompassing studies published between 2000 and 2024. Studies examining the composition of the microbiome, immune responses, and HPV-related outcomes were evaluated and synthesized into a comprehensive review. Results: A Lactobacillus-dominant microbiome, particularly with L. crispatus, creates a protective environment through lactic acid production, maintenance of low pH, and anti-inflammatory immune modulation, facilitating HPV clearance. Dysbiosis, often characterized by a dominance of L. iners and overgrowth of anaerobic bacteria, fosters chronic inflammation, cytokine imbalance, and a microenvironment conducive to HPV persistence and progression. Hormonal changes and menopause exacerbate these microbial shifts, increasing the risk of cervical lesions. Studies suggest that cytokine profiles and antimicrobial peptides significantly influence local immune responses, further modulating infection outcomes. Conclusions: The cervicovaginal microbiome is a critical determinant in HPV infection outcomes, with therapeutic potential for modulating the microbiome to enhance immune responses and prevent cervical cancer. Personalized microbiome-targeted therapies may offer a novel avenue for managing HPV and reducing cervical cancer incidence.