Molecular Pathogenesis of HPV in Cervical Cancer Opportunities for Targeting E6E7 Interactions
Year: 2025
Type: article
Abstract: Cervical cancer remains a leading cause of gynecologic malignancy worldwide, with high-risk human papillomavirus (HPV) infection—particularly HPV16 and HPV18—established as the primary etiological factor. HPV oncoproteins E6 and E7 are the key determinants in HPV-mediated carcinogenesis. They continually compromise the normal repression of the cell cycle, apoptotic programs, genomic stability, and immune surveillance by inactivating the tumor-suppressive capacities of p53 and retinoblastoma protein (pRb), thereby disrupting regulatory systems that have traditionally protected the organism against neoplasia. E6 and E7 not only act in these canonical pathways, but also reprogram the metabolism and chromatin structure of the host cell, modulate non-coding RNAs, and activate signaling pathways including PI3K/Akt, STAT3, Wnt/β-catenin, Hedgehog, and Notch, which in turn promote tumorigenesis and resistance to treatment. Advances in structural biology, particularly the elucidation of the E6/E6AP/p53 and E7/PTPN14 complexes, have made rational design of agents that disrupt these protein interactions possible. Investigational approaches currently in testing include small molecule inhibitors, peptide-based antagonists, affibody molecules, RNA interference, CRISPR/Cas-based genome editing, and immunotherapies such as E6/E7-targeted vaccines and engineered T-cell platforms, often in combination with immune checkpoint blockade. Preclinical findings indicate that E6/E7-targeted interventions have the potential to reinstate tumor-suppressor activity, induce apoptosis or senescence, stimulate an antitumor immune response, and improve sensitivity to conventional agents. However, clinical translation is complicated by delivery-related obstacles, tumor heterogeneity, immune escape, and off-target risks. More durable results may be possible with new combination regimens incorporating genome editing, metabolic inhibition, epigenetic manipulation, and immunity-based therapy. The next step is to refine delivery systems, develop dual-target inhibitors, identify robust biomarkers (e.g., circulating HPV DNA, PD-L1 expression, miRNA signatures), and stratify patients using multi-omics profiling to achieve precision, virus-targeted oncology in the future. This review summarizes recent advances in our understanding of the biology of E6/E7, along with a discussion of therapeutic opportunities and limitations in developing E6/E7-targeted therapeutic applications against HPV-related cervical cancer.
Author: Hossain, Md Ishtiak
Institution: Noida International University
Language: English
Subfield: Epidemiology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W6931108591
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