TIM3-targeted delivery of venetoclax overcomes drug resistance and reinvigorates NK cell activity in acute myeloid leukemia

  • Nat Cancer. 2026 Aug 12. doi: 10.1038/s43018-026-01217-z.
Qiwei Wang  #  1  2 ,  Jingyi Li  #  3  4 ,  Xin Zeng  #  3  4 ,  Lina Liu  #  3  4 ,  Huan Lu  #  3  4 ,  Yin Zhao  3  4 ,  Yan Huang  5 ,  Rui Wang  3  4 ,  Chen Wang  3  4 ,  Yingli Han  3  4 ,  Yishan Ye  3  4 ,  Yanmin Zhao  3  4 ,  Jimin Shi  3  4 ,  Yi Luo  3  4 ,  Weiyan Zheng  3  4 ,  Yongxian Hu  3  4 ,  Shibing Wang  6 ,  Xiangmin Tong  7 ,  He Huang  8  9 ,  Shanshan Pei  10  11 ,  Pengxu Qian  12  13
Affiliations
  • 1. Bone Marrow Transplantation Center of the First Affiliated Hospital, Center for Stem Cell and Regenerative Medicine, Liangzhu Laboratory, State Key Laboratory of Experimental Hematology, Zhejiang University School of Medicine, Hangzhou, China. [email protected].
  • 2. Institute of Hematology, Zhejiang Engineering Laboratory for Stem Cell and Immunotherapy, Zhejiang University, Hangzhou, China. [email protected].
  • 3. Bone Marrow Transplantation Center of the First Affiliated Hospital, Center for Stem Cell and Regenerative Medicine, Liangzhu Laboratory, State Key Laboratory of Experimental Hematology, Zhejiang University School of Medicine, Hangzhou, China.
  • 4. Institute of Hematology, Zhejiang Engineering Laboratory for Stem Cell and Immunotherapy, Zhejiang University, Hangzhou, China.
  • 5. School of Clinical Medicine, Chengdu Medical College, Chengdu, China.
  • 6. Zhejiang Key Laboratory of Zero Magnetic Medicine, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou, China.
  • 7. Zhejiang Key Laboratory of Zero Magnetic Medicine, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou, China. [email protected].
  • 8. Bone Marrow Transplantation Center of the First Affiliated Hospital, Center for Stem Cell and Regenerative Medicine, Liangzhu Laboratory, State Key Laboratory of Experimental Hematology, Zhejiang University School of Medicine, Hangzhou, China. [email protected].
  • 9. Institute of Hematology, Zhejiang Engineering Laboratory for Stem Cell and Immunotherapy, Zhejiang University, Hangzhou, China. [email protected].
  • 10. Bone Marrow Transplantation Center of the First Affiliated Hospital, Center for Stem Cell and Regenerative Medicine, Liangzhu Laboratory, State Key Laboratory of Experimental Hematology, Zhejiang University School of Medicine, Hangzhou, China. [email protected].
  • 11. Institute of Hematology, Zhejiang Engineering Laboratory for Stem Cell and Immunotherapy, Zhejiang University, Hangzhou, China. [email protected].
  • 12. Bone Marrow Transplantation Center of the First Affiliated Hospital, Center for Stem Cell and Regenerative Medicine, Liangzhu Laboratory, State Key Laboratory of Experimental Hematology, Zhejiang University School of Medicine, Hangzhou, China. [email protected].
  • 13. Institute of Hematology, Zhejiang Engineering Laboratory for Stem Cell and Immunotherapy, Zhejiang University, Hangzhou, China. [email protected].
  • # Contributed equally.
PMID: 42587178 DOI: 10.1038/s43018-026-01217-z
Abstract

Acute Myeloid Leukemia (AML) remains challenging, especially for older or unfit individuals who develop resistance to venetoclax (VEN)-based regimens. Although Tim3 represents a promising AML target, clinical blockade has yielded suboptimal outcomes. Here, we develop VINCENT (VEN-integrated natural killer cell engager targeting Tim3), a therapeutic platform combining anti-CD16 and anti-TIM3 antibodies with nanoformulated VEN. In VEN-resistant AML cell lines and patient-derived xenograft models, VINCENT overcomes resistance by enhancing VEN delivery, eliminating Tim3+ blasts and dysfunctional T cells and activating natural killer (NK) cells. In primary AML samples, VINCENT selectively kills drug-resistant blasts, with efficacy correlating with the NK cell-to-TIM3+ blast ratio. Single-cell transcriptomics reveals VINCENT depletes high-TIM3 blasts and remodels the immunosuppressive microenvironment toward immune competence. Collectively, VINCENT simultaneously addresses VEN resistance, NK cell dysfunction and immune evasion, offering a personalized option for elderly or unfit individuals with AML failing standard VEN regimens.

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