Killing the Killers: Natural Killer Cell Therapy Targeting Glioma Stem Cells in High-Grade Glioma

High-grade gliomas (HGGs), including glioblastoma (GBM) in adults and diffuse intrinsic pontine glioma (DIPG) in children, are among the most aggressive and deadly brain tumors. A key factor in their resilience is the presence of glioma stem cells (GSCs), which drive tumor initiation, progression, and resistance to treatment. Targeting and eradicating GSCs holds potential for curing both GBM and DIPG. Natural Killer (NK) cells, as part of the innate immune system, naturally recognize and destroy malignant cells. Recent advances in NK cell-based therapies, such as chimeric antigen receptor (CAR)-NK cells, NK cell engagers, and NK cell-derived exosomes, offer promising approaches for treating GBM and DIPG, particularly by addressing the persistence of GSCs. This review highlights these advancements, explores challenges such as the brain-blood barrier and the immunosuppressive tumor microenvironment, and proposes future directions for improving and clinically advancing these NK cell-based therapies for HGGs.