Authors: Qun Jiang, Weiming Yu, James Ma, Mingming Zhao, Jizhong Zou, Sameer Mir, Jingli Zhang, Ronald N. Germain, Raffit Hassan
Published: 2025-05-02
Source: Full article
Human induced pluripotent stem cells (iPSCs) offer a promising source for chimeric antigen receptor (CAR)–engineered natural killer (NK) products. However, complex iPSC-NK (iNK) manufacturing challenges clinical use. Here, we identified LiPSC-GR1.1 as a superior iPSC line for iNK production. By engineering LiPSC-GR1.1 with a mesothelin (MSLN)–targeting CAR and interleukin-15 (IL-15), we achieved robust differentiation of iPSCs into mature activated iNK cells with enhanced tumor killing efficacy, superior tumor homing, and vigorous proliferation. Single-cell transcriptomic analysis revealed that transforming growth factor–β (TGF-β)–producing tumor cells up-regulated major histocompatibility complex molecules and down-regulated MSLN post–CAR-IL-15 iNK treatment. Tumor-infiltrating CAR-IL-15 iNK cells exhibited high levels of CAR, IL-15, and NK-activating receptors, negligible checkpoint exhaustion markers, and extremely low levels of NK suppressive factors