Molecular Pathogenesis of HPV16‐Associated Cervical Cancer: From Viral Entry to Therapeutic Interventions

ABSTRACT Cervical cancer poses significant global health challenge, especially in low‐ and middle‐income countries. It is primarily caused by persistent infection with high‐risk human papillomavirus type 16 (HPV16). Disease progression from early infection to invasive cancer is multistep process driven by virus–host complex molecular interactions. This review presents molecular pathogenesis of HPV16‐driven cervical cancer, focusing on intricate mechanisms from virus entry to malignant transformation. It details the steps involved, from viral attachment on basement membrane to internalization through actin‐dependent endocytic pathway. Following internalization, virus hijacks host mitotic machinery and undergoes series of orchestrated steps to deliver viral genome to host nucleus. This review describes these steps including enzymatic priming by proteases and host chaperones, capsid uncoating endosomal system, L2‐mediated membrane penetration, and subsequent retrograde transport of viral genome‐protein complex to nucleus. It also explores functions of the driving oncogenes E6 and E7, which degrade two crucial tumor suppressor genes, p53 and pRb. The review highlights how constitutive expression of E6/E7, coupled with aneuploidy play key roles in uncontrolled cell division, genomic instability, cellular plasticity, and induction of epithelial–mesenchymal transition to promote cancer stem cell traits. Finally, the review focuses on therapeutic interventions for cervical cancer, including current prophylactic vaccines, screening programs, emerging therapeutic vaccines against E6/E7, small molecule inhibitors to impair viral life cycle, and advanced therapeutic modalities, including gene editing, immunotherapy, and nanotherapeutics. Thus, this review aims to provide researchers and clinicians with updated comprehensive knowledge on HPV16 pathogenesis, oncogenic transformation to cervical cancer, vaccination and therapeutic modalities, to enable the eradication of this disease.