biostudies-literatureShanley MNHLBI NIH HHSNCI NIH HHSNIH HHS1450-1466.e11https://www.ebi.ac.uk/biostudies/studies/S-EPMC11370652biostudies-literatureUnknown42(8)Glioblastoma (GBM) is an aggressive brain cancer with limited therapeutic options. Natural killer (NK) cells are innate immune cells with strong anti-tumor activity and may offer a promising treatment strategy for GBM. We compared the anti-GBM activity of NK cells engineered to express interleukin (IL)-15 or IL-21. Using multiple in vivo models, IL-21 NK cells were superior to IL-15 NK cells both in terms of safety and long-term anti-tumor activity, with locoregionally administered IL-15 NK cells proving toxic and ineffective at tumor control. IL-21 NK cells displayed a unique chromatin accessibility signature, with CCAAT/enhancer-binding proteins (C/EBP), especially CEBPD, serving as key transcription factors regulating their enhanced function. Deletion of CEBPD resulted in loss of IL-21 Cancer cellInterleukin-21 engineering enhances NK cell activity against glioblastoma via CEBPD.PMC11370652U01 CA247760S10 OD024977P30 CA016672R35 HL144805P50 CA127001Miao QMohanty VEvans SEFowlkes NWNunez Cortes AKDede MZaman MFZhang PLang FFRafei HShpall EJDaher MAcharya SJain AShanley MGumin JSingh SChen KDou JPantaleοn Garcιa JHicks SCUprety NJones CMHe SLi YLi SBasar RDeyter GMRezvani KLiu BXiong DShaim HLiu EMuniz-Feliciano LfalseInterleukin-21 engineering enhances NK cell activity against glioblastoma via CEBPD.Glioblastoma (GBM) is an aggressive brain cancer with limited therapeutic options. Natural killer (NK) cells are innate immune cells with strong anti-tumor activity and may offer a promising treatment strategy for GBM. We compared the anti-GBM activity of NK cells engineered to express interleukin (IL)-15 or IL-21. Using multiple in vivo models, IL-21 NK cells were superior to IL-15 NK cells both in terms of safety and long-term anti-tumor activity, with locoregionally administered IL-15 NK cells proving toxic and ineffective at tumor control. IL-21 NK cells displayed a unique chromatin accessibility signature, with CCAAT/enhancer-binding proteins (C/EBP), especially CEBPD, serving as key transcription factors regulating their enhanced function. Deletion of CEBPD resulted in loss of IL-21 2024-01-01T00:00:00Z2024 Aug2026-05-29T17:57:52.062Z2026-05-18T03:07:41.973ZS-EPMC113706523913772910.1016/j.ccell.2024.07.007