Targeting innate immunity to overcome immune evasion in HPV-associated cancers.
Human papillomavirus (HPV)-associated cancers provide a unique model for understanding the paradox of viral antigenicity and tumor immune escape. Although viral oncoproteins such as E6 and E7 generate non-self antigens, many HPV-associated tumors persist under immune pressure and show heterogeneous responses to immune checkpoint blockade. This discrepancy reflects a process in which persistent HPV infection and malignant transformation remodel innate immune sensing, interferon (IFN) signaling, antigen presentation, and the tumor microenvironment. These changes impair dendritic cell activation and cytotoxic immune priming while promoting chronic inflammation, myeloid polarization, T-cell exhaustion, and PD-1/PD-L1-mediated adaptive immune resistance. In this review, we discuss how HPV-associated cancers subvert antiviral innate immunity and how these processes contribute to immune evasion. We further highlight therapeutic strategies aimed at restoring antiviral antitumor immunity, including immune checkpoint blockade, STING agonists, therapeutic HPV vaccines, radiotherapy-based combinations, TGF-β pathway inhibition, and biomarker-guided treatment approaches. Understanding the links among viral pathogenesis, innate immune remodeling, and checkpoint evasion may support more rational immunotherapy combinations for HPV-associated malignancies.