# Natural killer cell dysfunction in glioma: from immune evasion to immunotherapy

## TL;DR

This paper reviews how natural killer cells are suppressed in gliomas and explores new immunotherapies to restore their tumor-fighting abilities.

## Contribution

The paper provides a comprehensive overview of NK cell dysfunction in gliomas and novel strategies like CAR-NK cells to enhance immunotherapy.

## Key findings

- Gliomas suppress NK cells via TME factors like TGF-β, IDO, and MDSCs.
- CAR-engineered NK cells targeting glioma markers show promise in preclinical models.
- Combining NK cell activation with immune checkpoint inhibitors is a promising therapeutic approach.

## Abstract

Natural killer (NK) cells, critical components of innate immunity, possess the ability to eliminate tumor cells without prior sensitization. In gliomas, particularly glioblastoma, the tumor microenvironment (TME) exerts potent immunosuppressive effects that impair NK cell function through MHC-I overexpression, secretion of TGF-β and IDO, and recruitment of myeloid-derived suppressor cells (MDSCs). Emerging evidence highlights the significance of NK cell infiltration, cytotoxicity, and ligand-receptor dynamics—such as NKG2D, KIRs, and CX3CR1+ subsets—in shaping prognosis and therapeutic responsiveness in glioma patients. Therapeutic strategies including activation of NK cells via chemotherapeutics (bortezomib, decitabine), blockade of inhibitory receptors (NKG2A, CD161), and combinatorial approaches with immune checkpoint inhibitors are under active investigation. Notably, chimeric antigen receptor (CAR)-engineered NK cells targeting EGFR, HER2, GD2, and CD133 show promise in preclinical glioma models due to their enhanced specificity and reduced toxicity compared to CAR-T cells. This review summarizes the multifaceted roles of NK cells in glioma immunity and highlights novel immunotherapeutic strategies to restore NK cell function and improve clinical outcomes.