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Targeting leukemic stem cell biomechanics suppresses stemness and enhances NK cell-mediated immunotherapy

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  • Mingming Zhu

    (University of Science and Technology of China, Department of Hematology, The First Affiliated Hospital of USTC, National Key Laboratory of Immune Response and Immunotherapy, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Division of Life Sciences and Medicine)

  • Haoxiang Yang

    (University of Science and Technology of China, The CAS Key Laboratory of Mechanical Behavior and Design of Materials, Department of Modern Mechanics)

  • Kailong Qiu

    (University of Science and Technology of China, The CAS Key Laboratory of Mechanical Behavior and Design of Materials, Department of Modern Mechanics)

  • Beibei Huang

    (University of Science and Technology of China, Department of Pathology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine)

  • Tingting Liang

    (University of Science and Technology of China, Department of Hematology, The First Affiliated Hospital of USTC, National Key Laboratory of Immune Response and Immunotherapy, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Division of Life Sciences and Medicine)

  • Yan Wang

    (University of Science and Technology of China, Department of Hematology, The First Affiliated Hospital of USTC, National Key Laboratory of Immune Response and Immunotherapy, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Division of Life Sciences and Medicine)

  • Huan Li

    (University of Science and Technology of China, Department of Hematology, The First Affiliated Hospital of USTC, National Key Laboratory of Immune Response and Immunotherapy, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Division of Life Sciences and Medicine)

  • Mingming Wu

    (University of Science and Technology of China, Department of Hematology, The First Affiliated Hospital of USTC, National Key Laboratory of Immune Response and Immunotherapy, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Division of Life Sciences and Medicine)

  • Xinru Liu

    (University of Science and Technology of China, Department of Hematology, The First Affiliated Hospital of USTC, National Key Laboratory of Immune Response and Immunotherapy, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Division of Life Sciences and Medicine)

  • Na Zhao

    (University of Science and Technology of China, Department of Hematology, The First Affiliated Hospital of USTC, National Key Laboratory of Immune Response and Immunotherapy, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Division of Life Sciences and Medicine)

  • Xian Song

    (University of Science and Technology of China, Department of Hematology, The First Affiliated Hospital of USTC, National Key Laboratory of Immune Response and Immunotherapy, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Division of Life Sciences and Medicine)

  • Xuxu Zhao

    (University of Science and Technology of China, Department of Obstetrics and Gynecology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine)

  • Mengqing Gao

    (University of Science and Technology of China, Department of Hematology, The First Affiliated Hospital of USTC, National Key Laboratory of Immune Response and Immunotherapy, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Division of Life Sciences and Medicine)

  • Yue Zhao

    (University of Science and Technology of China, Department of Hematology, The First Affiliated Hospital of USTC, National Key Laboratory of Immune Response and Immunotherapy, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Division of Life Sciences and Medicine)

  • Xiangting He

    (University of Science and Technology of China, Department of Hematology, The First Affiliated Hospital of USTC, National Key Laboratory of Immune Response and Immunotherapy, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Division of Life Sciences and Medicine)

  • Rui Zhao

    (University of Science and Technology of China, Department of Hematology, The First Affiliated Hospital of USTC, National Key Laboratory of Immune Response and Immunotherapy, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Division of Life Sciences and Medicine)

  • Lili Qian

    (University of Science and Technology of China, Department of Obstetrics and Gynecology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine)

  • Qinhua Liu

    (The First Affiliated Hospital of Anhui Medical University, Department of Hematology)

  • Changcheng Zheng

    (University of Science and Technology of China, Department of Hematology, The First Affiliated Hospital of USTC, National Key Laboratory of Immune Response and Immunotherapy, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Division of Life Sciences and Medicine)

  • Xiaoyu Zhu

    (University of Science and Technology of China, Department of Hematology, The First Affiliated Hospital of USTC, National Key Laboratory of Immune Response and Immunotherapy, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Division of Life Sciences and Medicine)

  • Hongyuan Jiang

    (University of Science and Technology of China, The CAS Key Laboratory of Mechanical Behavior and Design of Materials, Department of Modern Mechanics)

  • Fang Ni

    (University of Science and Technology of China, Department of Hematology, The First Affiliated Hospital of USTC, National Key Laboratory of Immune Response and Immunotherapy, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Division of Life Sciences and Medicine)

Abstract

Acute myeloid leukemia (AML) is primarily driven by leukemic stem cells (LSCs), the main cause of relapse and therapy resistance. Here, we discover that LSCs are predominantly small and mechanically soft. These mechanical properties enable their selective isolation using microfluidic chips. Single-cell RNA-sequencing of primary human AML bone marrow identifies enrichment of LSCs within the FSClow ALDH1A1+ subpopulation, which exhibits long-term stemness in functional assays. Notably, inhibiting ALDH1A1 in these cells promotes F-actin polymerization and increases cellular stiffness, reducing their stemness while enhancing their susceptibility to natural killer (NK) cell-mediated cytotoxicity. In AML patient-derived xenograft models, the combination of ALDH1A1 inhibition with NK cell therapy markedly suppresses leukemia progression. These findings suggest that targeting the mechanical properties of LSC offers a promising strategy to overcome AML treatment resistance, providing insights into stem cell mechanobiology and paving the way for combining targeted therapies with immunotherapy to improve clinical outcomes.

Suggested Citation

  • Mingming Zhu & Haoxiang Yang & Kailong Qiu & Beibei Huang & Tingting Liang & Yan Wang & Huan Li & Mingming Wu & Xinru Liu & Na Zhao & Xian Song & Xuxu Zhao & Mengqing Gao & Yue Zhao & Xiangting He & R, 2025. "Targeting leukemic stem cell biomechanics suppresses stemness and enhances NK cell-mediated immunotherapy," Nature Communications, Nature, vol. 16(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-65842-5
    DOI: 10.1038/s41467-025-65842-5
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