NK cells in HPV-related tumorigenesis: mechanisms and clinical applications

Human papillomavirus (HPV) infection is a major global health concern due to its association with various cancers, particularly cervical and head and neck squamous cell carcinomas. High-risk HPV types, such as HPV16 and HPV18, employ oncoproteins E6 and E7 to disrupt host cell regulatory pathways, promote immune evasion, and facilitate malignant transformation. Natural killer (NK) cells, critical components of innate immunity, play a pivotal role in surveilling and eliminating HPV-infected cells. However, HPV-mediated immune evasion mechanisms, including downregulation of MHC-I, suppression of chemokine signaling (e.g., CXCL14), and upregulation of inhibitory molecules (e.g., TIGIT, KLRG1), impair NK cell functionality. This review explores the intricate interactions between HPV and NK cells, highlighting the impact of HPV on NK cell infiltration, exhaustion, and receptor expression. Additionally, it discusses emerging therapeutic strategies to enhance NK cell activation, such as pharmacological agents (e.g., γ-PGA, α-GalCer), innate immune agonists (e.g., STING, RIG-I), genetic engineering (e.g., CAR-NK, iPSC-NK cells), and combination therapies with immune checkpoint inhibitors or monoclonal antibodies (e.g., cetuximab). Clinical applications, including adoptive NK cell transfer and biomarker-guided personalized immunotherapy, are also reviewed. Despite challenges like immunosuppressive tumor microenvironments and limited NK cell persistence, advancements in genetic engineering and nanoparticle delivery systems offer promising solutions. Future research should focus on integrating mechanistic insights with clinical trial design to optimize NK cell-based therapies for HPV-associated malignancies.