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

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, Rui Zhao, Lili Qian, Qinhua Liu, Changcheng Zheng, Xiaoyu Zhu, Hongyuan Jiang () and Fang Ni ()
Additional contact information
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

Nature Communications, 2025, vol. 16, issue 1, 1-19

Abstract: 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.

Date: 2025
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-025-65842-5 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-65842-5

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-025-65842-5

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().