Rewired DDR-TGF-β-β-catenin-PD-L1 axis accelerates progression and shapes therapy in human papillomavirus-driven cancer.

Understanding Human papillomavirus (HPV) oncogenic mechanisms is essential for developing preventive and therapeutic strategies and overcoming therapy resistance in HPV-related cancers. These challenges may arise from the ability of high-risk HPV to subvert host tumor suppressors such as p53 and Rb, and to drive oncogenesis through homologous recombination deficiency (HRD) and multi-network dysregulation. Mechanistically, HPV exerts context-dependent effects on the host DNA damage response (DDR). During episomal replication, E6/E7 activate DDR and recruit BRCA1/RAD51 to replication foci to support viral replication without significantly compromising host HR repair. Upon viral integration, however, sustained E6/E7 expression drives HRD and shifts DNA repair toward error-prone end joining, generating genomic instability that fuels malignant transformation. These alterations are most clearly established in cervical cancer, whereas evidence in HPV-positive non-cervical cancer is more variable and requires further context-specific validation. In parallel, HPV E6/E7 antagonize transforming growth factor-β (TGF-β)-mediated tumor suppression and, potentially through FAT Atypical Cadherin 4 (FAT4) down-regulation, engage Wnt/β-catenin signaling. The resultant elevation of nuclear β-catenin induces programmed death-ligand 1 (PD-L1) expression promotes immune evasion, stemness, and invasiveness. Of note, while the DDR-TGF-β-β-catenin-PD-L1 axis is backed by substantial evidence in HPV-related cancers, certain connections within this pathway are extrapolated from non-HPV models or general pathway biology and are explicitly denoted as such in the main text. With residual p53 activity, HRD may confer initial sensitivity to DNA-damaging agents, but resistance frequently develops-a pattern reminiscent of the initial response followed by acquired resistance observed with immunotherapies in HPV-related cancers. Integrating these mechanistic insights, we propose ablative therapies (e.g., ablation, photodynamic therapy, surgery) for cervical intraepithelial neoplasia (CIN), and for advanced or resistant disease, a synthetic-lethality framework combining genotoxic therapies with DDR inhibitors, targeting DDR-TGF-β-β-catenin-PD-L1 axis, and antiviral approaches. The proposed therapeutic strategies, however, should be interpreted with caution, as their evidence base varies across tumor types and warrants further investigation.