The hallmark of pediatric high-grade glioma is pervasive mis-splicing of microexons•Transcripts encoding NRCAM skip exons 5 and 19•Δex5Δex19, but not full-length NRCAM drives tumor growth in orthotopic glioma models•Δex5Δex19 NRCAM-selective mAb enables killing by T cells armed with the Fc receptor.