The Role of HPV and Hormone in Cervical Precancer and Cancer: Molecular Pathophysiology and Cell Biology of Disease and Treatment.

Cervical cancer remains a major global health challenge despite advances in human papillomavirus (HPV) vaccination, screening, and treatment. Persistent infection with high-risk HPV types, particularly HPV16 and HPV18, is a necessary cause of cervical cancer; however, only a small fraction of infections progress to malignancy, indicating the importance of additional cofactors. Increasing evidence identifies estrogen signaling as a critical modifier of HPV-driven carcinogenesis. Estrogen acts synergistically with HPV oncogenes E6 and E7 to promote genomic instability, immune evasion, and tumor progression, largely through effects on the tumor microenvironment (TME). This review aims to clarify and summarize current knowledge on the interplay between HPV biology, estrogen signaling, and the cervical cancer microenvironment, discussing HPV structure, life cycle, and mechanisms of oncogenesis including viral genome integration, disruption of tumor suppressor pathways, and induction of chromosomal instability. Particular emphasis is placed on estrogen receptor signaling, highlighting the shift from tumor cell-intrinsic estrogen receptor α (ERα) expression to a paracrine, stromal-driven mechanism during disease progression. Estrogen signaling in cancer-associated fibroblasts, myeloid-derived suppressor cells, and regulatory T cells fosters an immunosuppressive microenvironment that supports viral persistence and malignant transformation. Both classical genomic and rapid non-genomic estrogen pathways are discussed, as well as their roles in immune modulation and DNA damage responses. Furthermore, there is emerging evidence linking estrogen signaling to HPV-induced genomic instability through pathways involving G protein-coupled estrogen receptor 1 (GPER1), estrogen receptor α36 (ERα36), High Mobility Group AT-Hook 2 (HMGA2), and wings apart-like (WAPL). Finally, the review contextualizes these molecular insights within contemporary clinical management, summarizing standard treatments and recent advances in targeted and immunotherapies, including bevacizumab and pembrolizumab. Understanding estrogen-driven stromal-immune crosstalk in HPV-associated cervical carcinogenesis may uncover novel therapeutic opportunities. Integrating hormonal modulation with immunotherapy and other targeted strategies represents a promising avenue to improve outcomes, particularly in advanced and treatment-resistant disease.