Host chromatin architecture in HPV-driven cervical cancer: molecular mechanisms and therapeutic resistance

Persistent infection with high-risk human papillomavirus (HPV) is the principal etiologic driver of cervical cancer. However, HPV status and E6/E7-mediated disruption of the p53/RB axis do not fully explain why HPV-associated lesions differ in persistence, malignant progression, therapeutic response, and relapse. This review examines how host chromatin architecture and related transcriptional programs may contribute to the stabilization of malignant cell states following HPV-mediated checkpoint disruption. We discuss evidence linking HPV persistence and integration to epigenetic permissiveness, three-dimensional genome organization, enhancer-promoter rewiring, cohesin dynamics, and WAPL-associated chromatin regulation. Particular attention is given to how these mechanisms may influence MYC/E2F-centered proliferative output and cooperate with context-dependent signaling and tumor microenvironmental adaptation to contribute to treatment tolerance and resistant malignant states. We also consider how chromatin-informed biomarkers, public datasets, perturbation-guided prioritization, authenticated cervical cancer cell lines, organoids, and patient-derived models can be used to evaluate therapeutically relevant vulnerabilities. By integrating viral oncogenesis with host genome regulation and adaptive resistance, this review proposes a conceptual and experimentally testable framework for stratifying HPV-driven cervical cancer and prioritizing candidate intervention nodes.