Pluripotent stem cell-derived CAR-NK progenitor therapy targets minimal residual disease and prevents relapse in leukemia models

  • Cell Stem Cell. 2026 Mar 5;33(3):405-420.e6. doi: 10.1016/j.stem.2026.01.013.
Zhiqian Wang  1 ,  Leqiang Zhang  1 ,  Dehao Huang  2 ,  Chengxiang Xia  2 ,  Qitong Weng  3 ,  Yunqing Lin  1 ,  Yanhong Liu  3 ,  Zhenghan Liu  4 ,  Ruowen Yi  1 ,  Fan Zhang  1 ,  Yaoqin Zhao  1 ,  Jiaxin Wu  1 ,  Hanmeng Qi  2 ,  Lijuan Liu  5 ,  Yiyuan Shen  2 ,  Yi Chen  2 ,  Yanping Zhu  5 ,  Tongjie Wang  6 ,  Mengyun Zhang  7 ,  Fangxiao Hu  8 ,  Jinyong Wang  9
Affiliations
  • 1. State Key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 101408, China.
  • 2. Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China.
  • 3. State Key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.
  • 4. State Key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; School of Life Science, Northeast Agricultural University, Harbin 150030, China.
  • 5. State Key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China.
  • 6. State Key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China. Electronic address: [email protected].
  • 7. State Key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China. Electronic address: [email protected].
  • 8. Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China. Electronic address: [email protected].
  • 9. State Key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 101408, China; Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China. Electronic address: [email protected].
PMID: 41742420 DOI: 10.1016/j.stem.2026.01.013
Abstract

Reducing relapse rates post-chemotherapy remains a major challenge for improving Cancer therapy. Here, we developed a pluripotent stem cell-derived induced natural killer (NK) lineage-committed progenitor (iNKP) cell therapy in leukemia models. We generated abundant iNKP cells via an Organoid culture system. The iNKP cells, engineered to express C-X-C motif Chemokine Receptor 4 (CXCR4) and chimeric antigen receptors (CARs), efficiently migrated to the bone marrow and generated CAR-iNK cells, which persisted in multiple organs and peripheral blood for over 80 days. Notably, CAR-iNKP cell infusion precisely protected Animals from tumor challenges. Furthermore, a single low-dose infusion of CAR-iNKP cells following conventional chemotherapy reduced minimal residual disease and significantly prevented Cancer relapse in human CD19+ B-ALL and CD7+ T-ALL tumor-bearing Animals. CAR-iNKP cell treatment addresses the limitations of traditional CAR-NK cell infusion and offers a new strategy for future application in human Cancer therapy.

Keywords
CAR-NK progenitor therapy; CXCR4; cancer minimal residual disease; chemotherapy; persistence; pluripotent stem cell.
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