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Natural killer (NK) cell therapy is a promising immunotherapeutic strategy; yet, its efficacy remains limited. We evaluated FT538, a clinical-grade NK product derived from induced pluripotent stem cells (iPSCs), in glioblastoma models.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>FT538, engineered with a high-affinity noncleavable CD16 Fc receptor, a membrane-bound IL-15\/IL-15R\u03b1 fusion protein, and CD38 knockout, was tested against 13 patient-derived glioblastoma stem-like cells (GSCs) in vitro and in orthotopic xenograft models. Intracranial persistence and neurotoxicity were assessed in mice. Surface proteomics identified therapeutic targets, and a B7-H3\u2013targeted tri-specific killer engager (TriKE) was evaluated with FT538 and NKG2C+ adaptive NK cells.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Glioblastoma stem-like cells were classified as sensitive (38%), moderately sensitive (38%), or resistant (23%) to FT538. Intracranial administration in mice was well tolerated, persisted for at least 35 days, and caused no neurotoxicity. A single intratumoral dose induced complete regression in sensitive xenografts. Surface profiling identified B7-H3 as a target to overcome resistance. Combination therapy with FT538 and a B7-H3 TriKE enhanced antitumor efficacy in resistant models, an effect also observed with adaptive NK cells.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>FT538 exhibits potent tumoricidal activity in 77% of GSC lines (NK-sensitive and moderately sensitive), with curative potential in sensitive models, and demonstrates favorable persistence and tolerability in vivo. B7-H3\u2013targeted TriKE restores NK sensitivity in resistant tumors. These findings provide a strong preclinical rationale for further clinical evaluation of FT538, alone or combined with B7-H3\u2013targeted TriKE, for glioblastoma and other solid tumors.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/neuonc\/noag154","type":"journal-article","created":{"date-parts":[[2026,7,11]],"date-time":"2026-07-11T11:53:22Z","timestamp":1783770802000},"page":"2369-2383","source":"Crossref","is-referenced-by-count":1,"title":["Induced pluripotent stem cell-derived natural killer cell therapy induces durable responses in glioblastoma and overcomes resistance via a B7-H3\u2013targeted tri-specific killer engager"],"prefix":"10.1093","volume":"28","author":[{"given":"Jian-Fang","family":"Ning","sequence":"first","affiliation":[{"name":"Department of Neurosurgery, University of Minnesota , Minneapolis, Minnesota,","place":["USA"]},{"name":"Masonic Cancer Center, University of Minnesota , Minneapolis, 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