Bacterial co-infection as a catalyst in HPV-associated cervical carcinogenesis

Abstract

Cervical cancer remains a preventable yet persistent global burden, with more than 660 000 new cases and 360 000 deaths reported in 2024. While high-risk HPV is the central driver of malignant transformation, growing evidence shows that bacterial co-infection can intensify HPV persistence and promote genomic instability. Meta-analyses now indicate that pathogens such as Chlamydia trachomatis, Mycoplasma genitalium, Gardnerella vaginalis, and diverse anaerobic microbiota markedly increase the risk of persistent HPV infection and cervical lesions. These microbes disrupt epithelial barriers, fuel chronic inflammation, and enhance the oncogenic activity of HPV E6/E7. Studies also show that Lactobacillus-depleted vaginal communities carry higher viral loads and increased CIN2⁺ progression. A 2024 review from sub-Saharan Africa further highlights frequent bacterial co-infections among HPV-positive women, particularly in settings with limited vaccination and screening. Together, these findings support a dual-pathogen model of cervical carcinogenesis and underscore the need to integrate microbiome-focused strategies into prevention efforts.

Dear Editor,

Cervical cancer remains one of the most preventable yet persistent malignancies worldwide, with GLOBOCAN 2024 reporting over 660 000 new cases and 360 000 deaths annually, making it the fourth most common cancer among women globally^[1^]. While high-risk human papillomavirus (HPV) infection is a well-established driver of malignant transformation, emerging evidence suggests that bacterial co-infection acts as a critical catalyst, amplifying HPV persistence, accelerating genomic instability, and enhancing malignant progression.

Recent systematic analyses have reinforced this link. A 2023 meta-analysis of 27 studies demonstrated that women with co-existing bacterial pathogens, particularly Chlamydia trachomatis, Mycoplasma genitalium, Gardnerella vaginalis, and high-diversity anaerobic microbiota, had 1.8–3.2-fold increased odds of persistent high-risk HPV infection^[2^]. Similarly, a recent 2025 meta-analysis of 17 observational studies showed that BV-associated genera, Gardnerella, Prevotella, Sneathia, Atopobium, and Streptococcus were significantly more abundant in women with high-risk HPV, CIN, and cervical cancer^[3^].

Bacterial co-infections are now recognized as biological accelerators of the HPV-driven carcinogenic cascade. C. trachomatis promotes double-strand DNA breaks, impaired repair pathways, and chromosomal instability, creating a permissive environment for HPV16/18 oncoprotein integration^[4^]. Anaerobic dysbiosis induces chronic mucosal inflammation, IL-6-NFκB signaling, and increased ROS, which potentiate the oncogenic actions of HPV E6/E7. Additionally, M. genitalium disrupts epithelial tight junctions, facilitating viral entry and enabling long-term viral persistence^[5^].

Microbiome-focused studies further demonstrate that Lactobacillus-depleted vaginal ecosystems exhibit higher viral loads and progression rates. A pooled analysis of over 5800 women across eight cohorts (2022–2024) showed that Lactobacillus crispatus–dominant microbiota reduced HPV persistence by nearly 40%, whereas high-diversity, BV-associated communities increased the risk of CIN2⁺ lesions^[6^]. This reinforces the concept that bacterial communities modulate the local immune microenvironment, shaping HPV oncogenic potential.

A 2024 review from sub-Saharan Africa reported that women with HPV often carry additional cervicovaginal pathogens such as Prevotella, Porphyromonas, and Trichomonas vaginalis, suggesting that microbial co-infections may quietly accelerate cervical disease, especially in settings where HPV vaccination and screening remain limited^[7^].

Collectively, these findings highlight a dual-pathogen model of cervical carcinogenesis, where HPV acts as the principal oncogenic stimulus and bacterial co-infection functions as an accelerant. Incorporating microbiome profiling, bacterial diagnostics, and targeted antimicrobial strategies into cervical cancer prevention may significantly improve outcomes. There is a pressing need for prospective longitudinal studies and randomized trials to define causality, clarify microbial signatures of progression, and evaluate microbiome-modifying interventions. This study followed the Transparency in the Reporting of Artificial Intelligence (TITAN) guidelines 2025^[8^].

Ethical approval

Not applicable.

Consent

Consent for publication is not applicable, as this study involves publicly available data.

Sources of funding

The authors received no funding.

Author contributions

M.S.M.: conceptualization, methodology, software, data curation, writing – original draft, reviewing and editing; T.Q.: software, data curation, writing – original draft, reviewing and editing; F.A.: writing – original draft, reviewing and editing; N.D.: reviewing and editing.

Conflicts of interest disclosure

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Research registration unique identifying number (UIN)

Not applicable.

Guarantor

Naseeb Danaf.

Provenance and peer review

Not commissioned.