The interplay between HPV, vaginal microbiota and host immunity in cervical carcinogenesis

Discover Oncology https://doi.org/10.1007/s12672-026-05169-9 Article in Press The interplay between HPV, vaginal microbiota and host immunity in cervical carcinogenesis Nima Afshar Moghaddam, Aria Mohabbat, Maryam Pourdehghan Jigheh, Ametis Mahboubi, Zahra Zenderuh Ravanlo, Dariush Shanehbandi, Somayeh Shokri & Hossein Bannazadeh Baghi Received: 29 November 2025 Accepted: 30 April 2026 Cite this article as: Moghaddam N.A., Mohabbat A., Jigheh M.P. et al. The interplay between HPV, vaginal microbiota and host immunity in cervical carcinogenesis. Discov Onc (2026). https://doi.org/10.1007/ s12672-026-05169-9 A We are providing an unedited version of this manuscript to give early access to its findings. Before final publication, the manuscript will undergo further editing. Please note there may be errors present which affect the content, and all legal disclaimers apply. E R P S S If this paper is publishing under a Transparent Peer Review model then Peer Review reports will publish with the final article. I T R E L C IN © The Author(s) 2026. Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/. ARTICLE IN PRESS 1 The Interplay between HPV, Vaginal Microbiota and Host Immunity in Cervical 2 Carcinogenesis 3 Nima Afshar Moghaddam1, Aria Mohabbat2,3, Maryam Pourdehghan Jigheh2,3, Ametis Mahboubi4, Zahra 4 Zenderuh Ravanlo2,3, Dariush Shanehbandi1, Somayeh Shokri5,6, Hossein Bannazadeh Baghi1,2,3* 5 6 1. Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran 7 2. Infectious and Tropical Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, 8 9 Iran 3. Department of Virology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran 10 4. Faculty of Veterinary, Tabriz Branch Medical Sciences, Islamic Azad University, Tabriz, Iran 11 5. Infectious Disease Research Center, Avicenna Institute of Clinical Sciences, Hamadan University 12 13 14 of Medical Sciences, Hamadan, Iran 6. S S E R P Department of Virology, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran 15 IN E L C 16 *Corresponding author: 17 Hossein Bannazadeh Baghi (Associate Prof.) 18 Department of Virology, Faculty of Medicine 19 Tabriz University of Medical Sciences. 20 Tabriz, Iran. 21 Tel (office): +98(41) 3336 4661 22 Email: and I T AR 23 24 25 26 1 ARTICLE IN PRESS 27 Abstract 28 Cervical cancer (CC) remains a major global health challenge, largely driven by persistent 29 infection with high-risk human papillomavirus (HPV) genotypes. Emerging evidence suggests that 30 the interplay between HPV, the vaginal microbiota (VM), and host immune responses critically 31 influences viral persistence and disease progression. In particular, dysbiotic VM marked by 32 reduced Lactobacillus dominance and increased prevalence of anaerobic bacteria such as 33 Gardnerella, Sneathia, Prevotella, and Atopobium—can impair HPV clearance, promote chronic 34 inflammation, and facilitate progression from cervical intraepithelial neoplasia (CIN) to invasive 35 carcinoma. Understanding these tripartite interactions offers opportunities for novel preventive 36 and therapeutic strategies, including microbiome modulation, immunotherapy, and gene editing. 37 This review highlights the potential of microbiome-targeted interventions to enhance immune 38 responses against HPV and reduce the burden of CC, although the underlying causal mechanisms 39 require further investigation in prospective studies. 40 41 42 43 44 IN E L C S S E R P Keywords: Vaginal Microbiota, HPV, Immune Responses, Cervical Cancer, Inflammation I T AR 45 46 47 48 49 50 51 52 2 ARTICLE IN PRESS 53 1. Background 54 The Human Papillomavirus (HPV) is a leading factor in the development of genital warts and 55 cervical cancer (CC), making it the most common sexually transmitted infection (1). It is essential 56 to differentiate between low-risk (LR-HPV) genotypes (e.g., HPV-6 and -11), which typically 57 cause benign genital warts, and high-risk (HR-HPV) genotypes (e.g., HPV-16 and -18) (2). HPV 58 is linked to 5% of all cancers worldwide, which includes cervical, anal, penile, vaginal, vulvar, and 59 oropharyngeal cancers. Among these, CC has the most significant impact, resulting in 60 approximately 260,000 deaths each year. Even with the HPV vaccine accessible, the projected 61 effects of CC remains significant over the next 3–5 decades because of inadequate vaccination 62 levels in low to middle-income countries and the absence of proper CC screening on a global scale 63 (3, 4). Despite initiatives aimed at promoting preventive vaccination of HPV among young 64 females, CC continues to be the fourth most prevalent cancer affecting sexually active women 65 worldwide (5). Approximately 90% of women can eliminate HPV infections on their own within 66 a timeframe of 6 to 18 months, and there are very few instances of progression from precancerous 67 lesions to invasive CC (6). Several studies have suggested that the mechanisms of host defense, 68 the composition of the genital microbiome, and various other elements within the female genital 69 tract contribute to the clearance and persistence of HPV, as well as the associated chance of 70 developing CC (7-9). 71 The innate and acquired immune responses form the essential barrier of host protection at the 72 mucosal surface against infections such as HPV (10). A variety of research has shown a correlation 73 between genital mucosal cytokine levels and the management or eradication of HPV infection in 74 the CC (8, 11, 12). It is proposed that the cytokine response initiates within days following the 75 onset of an HPV infection and is later diminished once effective clearance of HPV is accomplished 76 by the appropriate effector cells (6). The primary reaction to HPV infection involves mature 77 antigen-presenting cells (APCs) that release cytokines an (...truncated)