Emily Nicole Marr

Background: Cervical cancer is one of the leading causes of cancer-related mortality in women worldwide, with over 500,000 new cases diagnosed annually¹. Infection with high-risk human papillomavirus (HPV) is associated with almost 100% of cervical cancer cases². Although approximately 90% of HPV infections are resolved by the immune system within two years², persistent infection can lead to chronic inflammation, cervical dysplasia, and cervical cancer³. HPV proteins E6 and E7 promote malignant transformation by suppressing the p53 and pRB pathways that govern inflammation and cellular defenses¹. Toll-like receptors are components of the innate immune system that recognize pathogens and danger damaged molecular patterns. TLR4 has been implicated in inflammatory signaling pathways involved in tumor growth, immune modulation¹ and chemotherapy resistance⁴. However, the role of TLR4 signaling throughout the progression of cervical cancer is not well understood.

Objective: In this narrative review, we explored the role of TLR4 signaling in HPV-associated cervical cancer progression, chemotherapy resistance, and its potential as a therapeutic target.

Search Methods: An online search on Google Scholar was conducted from 2017 to 2026 using the following keywords: “TLR4”, “HPV”, and “cervical cancer”.

Results: Studies indicated that TLR4 signaling contributes to cervical cancer progression through activation of the inflammatory pathway^1-4. A study using mouse models and HeLa and CaSki human cervical cancer cell lines showed that TLR4 silencing significantly reduced tumor size and expression of iNOS, IL-6, MIP3α, and VEGF¹. A study using a TLR4 knockout HeLa cells found that HeLa cells were 45% less proliferative and 35% less viable⁴. The ability of the knockout TLR4 HeLa cells to form colonies and migrate was also affected⁴. These cell lines showed a significant increase in apoptosis when treated with a chemotherapeutic agent, suggesting that TLR4 contributes to chemotherapy resistance⁴. Mice with mouse cervical cancer cell lines were treated with Icariin, a plant flavonoid, which reduced cell migration and invasion and increased apoptosis⁵. An additional study examined cervical biopsies from patients with either high-grade squamous intraepithelial lesions (H-SIL) or squamous cell carcinoma (SCC), showing increased TLR4 expression in H-SIL specimens and reduced TLR4 expression in SCC specimens³. This demonstrated stage-dependent changes in TLR4 expression during cervical cancer progression³.

Conclusions: Current studies support a significant role for TLR4 signaling in cervical cancer progression, spanning inflammatory signaling pathways, tumor survival, migration, and chemotherapy resistance. TLR4’s stage-dependent expression provides multiple opportunities to modulate TLR4 activity. Decreasing TLR4 in cervical cancer could allow for improved chemotherapy response, creating more opportunities to reduce cancer progression and improve patient outcomes.

Works Cited:

1. Jiang N, Xie F, Chen L, Chen F, Sui L. The effect of TLR4 on the growth and local inflammatory microenvironment of HPV-related cervical cancer in vivo. Infectious Agents and Cancer. 2020;15(1). doi:10.1186/s13027-020-0279-9
2. Dogan S, Terzioglu E, Ucar S. Innate immune response against HPV: Possible crosstalking with endocervical γδ T cells. Journal of Reproductive Immunology. 2021;148:103435. doi:10.1016/j.jri.2021.103435
3. Santoro A, Angelico G, Arciuolo D, et al. TLR4 downregulation identifies high-risk HPV infection and integration in H-sil and squamous cell carcinomas of the uterine cervix. Current Issues in Molecular Biology. 2024;46(10):11282-11295. doi:10.3390/cimb46100670
4. Morale MG, Tamura RE, Cintra R, Araújo NM, Villa LL. TLR4 and SARM1 modulate survival and chemoresistance in an HPV-positive cervical cancer cell line. Scientific Reports. 2022;12(1). doi:10.1038/s41598-022-09980-6
5. Li C, Yang S, Ma H, Ruan M, Fang L, Cheng J. Influence of icariin on inflammation, apoptosis, invasion, and tumor immunity in cervical cancer by reducing the TLR4/myd88/NF-ΚB and Wnt/β-catenin pathways. Cancer Cell International. 2021;21(1). doi:10.1186/s12935-021-01910-2