Induced Pluripotent Stem Cell-Derived NK Cells as an Off-the-Shelf Platform for Cancer Immunotherapy: Opportunities, Challenges, and Clinical Translation.

In recent years, off-the-shelf cellular immunotherapies have attracted much attention as a practical alternative to autologous therapies. Within this landscape, induced pluripotent stem cell-derived natural killer cells (iPSC-derived NK cells; iPSC-NK) have emerged as a highly versatile platform because they combine renewable starting material, batch-to-batch uniformity, favorable intrinsic safety, and amenability to precise genetic engineering.This review places iPSC-NK cells within the broader field of NK cell-based immunotherapy by comparing them with peripheral blood-derived NK cells, umbilical cord blood-derived NK cells, and NK cell lines, including clinically explored NK-92-based platforms, and by outlining key distinctions between NK cell therapies and CAR-T approaches. We summarize current strategies for iPSC-to-NK differentiation, spanning feeder-based systems, feeder-free protocols, embryoid body approaches, and scalable GMP-compatible manufacturing methods. We further discuss genetic engineering strategies for NK cells, with particular emphasis on genetic tuning as a systems-level framework for coordinating CAR signaling, cytokine responsiveness, and activation-inhibition balance to improve antitumor efficacy while preserving functional stability and clinical safety. In addition, this review examines translational challenges that continue to limit broader NK-cell adoption, including incomplete functional maturation, limited persistence, donor- and source-dependent variability, manufacturing standardization, cryopreservation, and quality-control requirements. Early clinical studies of iPSC-NK products indicate a favorable safety profile and preliminary antitumor activity in selected hematologic malignancies, although durable efficacy and broader validation in solid tumors remain to be established. Importantly, iPSC-NK cells should be considered one of several complementary NK-cell platforms rather than a definitive or universally superior strategy. Overall, current evidence supports iPSC-NK cells as a promising programmable off-the-shelf platform, but their ultimate clinical impact will depend on achieving reproducible large-scale manufacturing, balanced genetic engineering, and consistent in vivo performance relative to other NK-cell sources and established CAR-T therapies.