# Natural killer cell exhaustion in ovarian cancer: from molecular suppression to therapeutic revival

## TL;DR

This paper reviews how ovarian cancer suppresses natural killer cells and explores new therapies to restore their ability to fight cancer.

## Contribution

The paper provides a systematic review of molecular pathways and therapeutic strategies to reverse NK cell exhaustion in ovarian cancer.

## Key findings

- Ovarian cancer creates an immunosuppressive environment that impairs NK cell cytotoxicity.
- NK cell dysfunction is driven by cytokines, ligand shedding, immune checkpoints, and metabolic changes.
- Emerging therapies like cytokine modulation and checkpoint blockade show promise in restoring NK cell function.

## Abstract

Ovarian cancer remains one of the most lethal gynecologic malignancies, largely due to its late-stage diagnosis and the establishment of an immunosuppressive tumor microenvironment (TME). Natural killer (NK) cells, key effectors of innate immunity, exhibit impaired cytotoxicity within this hostile niche. The dysfunction arises from multiple mechanisms, including suppression by immunosuppressive cytokines (TGF-β, MUC16), shedding of activating ligands (MICA/B, B7-H6, CD155), overexpression of inhibitory immune checkpoints (PD-1, TIGIT), and metabolic reprogramming shaped by glucose and lipid competition. Recent advances in NK cell–based immunotherapies—such as cytokine modulation, adoptive NK transfer, and checkpoint blockade—have demonstrated potential to reverse NK exhaustion and enhance antitumor efficacy. In this review, we systematically dissect the molecular and cellular pathways underlying NK cell suppression in ovarian cancer and evaluate emerging strategies to reinvigorate NK-mediated immunosurveillance.