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

## TL;DR

This paper reviews how HPV evades NK cells and explores new therapies to enhance NK cell-based treatments for HPV-related cancers.

## Contribution

The paper provides a comprehensive overview of HPV's immune evasion mechanisms and novel strategies to boost NK cell activity in HPV-related cancers.

## Key findings

- HPV oncoproteins E6 and E7 disrupt host pathways and impair NK cell function through MHC-I downregulation and chemokine suppression.
- Therapeutic approaches like CAR-NK cells, iPSC-NK cells, and immune agonists show promise in enhancing NK cell activation against HPV.
- Combination therapies with checkpoint inhibitors and monoclonal antibodies are being explored to improve clinical outcomes in HPV-associated malignancies.

## Abstract

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.