• IL-21-overexpressing NK cells demonstrate superior and sustained anti-tumor activity against glioblastoma stem cells compared to IL-15, especially upon repeated challenges.
• A single intratumoral injection of IL-21 NK cells achieves long-term tumor eradication and significantly prolongs survival in orthotopic patient-derived GBM mouse models.
• IL-21 NK cells exhibit reduced toxicity in vivo, avoiding the severe weight loss and potential oncogenic risks associated with IL-15 overexpression.
• Continuous local secretion of IL-21 by genetically modified NK cells is crucial for efficacy, as short-term priming with recombinant IL-21 fails to control GSC growth.