Targeting leukemic stem cell biomechanics suppresses stemness and enhances NK cell-mediated immunotherapy
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 FSC<sup>low</sup> ALDH1A1<sup>+</sup> 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.
Authors
- Kailong Qiu (ORCID: https://orcid.org/0000-0002-8175-831X)
- Xuxu Zhao
- Fang Ni (ORCID: https://orcid.org/0000-0003-3680-8856)
- Changcheng Zheng (ORCID: https://orcid.org/0000-0002-1976-6415)
- Xiangting He (ORCID: https://orcid.org/0009-0007-1357-4432)
- Xian Song
- Mengqing Gao
- Yue Zhao (ORCID: https://orcid.org/0000-0001-8983-0024)
- Mingming Wu (ORCID: https://orcid.org/0000-0001-8420-3750)
- Beibei Huang (ORCID: https://orcid.org/0000-0003-4922-1309)
- X. Liu (ORCID: https://orcid.org/0009-0006-2931-0872)
- Qinhua Liu (ORCID: https://orcid.org/0000-0002-3218-046X)
- Huan Li (ORCID: https://orcid.org/0000-0003-0736-9292)
- Yan Wang (ORCID: https://orcid.org/0000-0003-2563-255X)
- Rui Zhao (ORCID: https://orcid.org/0000-0001-5208-1672)
- Na Zhao (ORCID: https://orcid.org/0000-0002-3418-6873)
- Xiaoyu Zhu (ORCID: https://orcid.org/0000-0002-4485-1478)
- Lili Qian (ORCID: https://orcid.org/0000-0002-6058-7355)
- Hongyuan Jiang (ORCID: https://orcid.org/0000-0003-0266-3011)
- Tingting Liang (ORCID: https://orcid.org/0000-0003-1370-3672)
- Haoxiang Yang (ORCID: https://orcid.org/0000-0003-0409-3753)
- Mingming Zhu (ORCID: https://orcid.org/0009-0008-8806-3466)
Institutions
- University of Science and Technology of China (CN)
- Anhui Medical University (CN)
- First Affiliated Hospital of Anhui Medical University (CN)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-12-01
- DOI
- https://doi.org/10.1038/s41467-025-65842-5
- Primary Topic
- Cellular Mechanics and Interactions
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- National Natural Science Foundation of China
- Chinese Academy of Sciences
- University of Science and Technology of China
- Fundamental Research Funds for the Central Universities