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Reprogramming endogenous NK circuits by highly efficient nonviral genome editing
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DOI：10.1084/jem.20260192.png)
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Abstract
En 中文
Natural killer (NK) cells are promising platforms for off-the-shelf immunotherapy, yet nonviral precision engineering remains limited by poor HDR efficiency, DNA toxicity, and manufacturing challenges. The aim of this study was to establish a high-yield, nonviral knock-in platform. Through extensive in-depth rational screens, we achieved similar to 90% HDR insertion of therapeutic payloads while maintaining 100% postediting recovery. By hijacking endogenous transcriptional programs, we installed genetic circuits into defined genomic loci to tune transgene expression. To enable context-dependent therapeutic responses, we integrated a synthetic positive feedback circuit at the CISH locus, which enhanced NK cell persistence and drove strong expression of anti-CD22/19 dual CAR. A hypoxia-responsive IL-12 circuit gated by the PFKFB4 promoter restored cytotoxicity under environmental stress. Finally, we showed this platform is compatible with GMP manufacturing and supports clinical- scale expansion. These findings provide a scalable framework for programmable, nonviral editing of NK cell effector functions for therapeutic and research applications.
Keywords:
CHIMERIC ANTIGEN RECEPTORS
NATURAL-KILLER-CELLS
T-CELLS
CHECKPOINT
LYMPHOMA
THERAPY
PROTEIN
CISH
Journal
J
IF:
10.6
Papers:
2.4W
Citations:
6.2W