Volume 36, No 3, Mar 2026

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 36 Issue 3, March 2026: 197-218   |  Open Access

ORIGINAL ARTICLES

Dynamic magneto-mechanical force in lysosomes induces durable macrophage repolarization for antitumor immunity

up>1,2,3,4,†,* , Mengge Zheng^5,† , Zhenyan Zhu^6,† , Yajuan Zhang^7,† , Peng Ning^2,3,4 , Haotian Chen^2,3,4 , Rui Gao^2,3,4 , Chang Xu^2,3,4 , Xueyan Wei^2,3,4 , Yali Liu^2,3,4 , Yingying Wang^2,3,4 , Ruimei Zhou^2,3,4 , Yuan Li^2,3,4 , Zhenguang Li^2,3,4 , Cheng Lv^2,3,4 , Chen Liu⁸ , Junfang Xu⁵ , Zihan Guo^1,2,3,4 , Zhixiang Hu^1,2,3,4 , Lan Fang⁹ , Ke Wei¹⁰ , Mengying Feng¹⁰ , Changshi Zhou^11,12 , Yunlang She¹ , Weiyan Sun¹ , Erzhen Chen^2,3,4 , Gustavo R. Plaza¹³ , Bin He^11,12 , Jason Miska¹⁴ , Weiwei Yang^8,15,* , Yichao Tang^6,* , Haipeng Liu^5,* , Chang Chen^1,* , Yu Cheng^2,3,4

¹Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China
²Translational Research Institute of Brain and Brain-Like Intelligence, Shanghai Fourth People’s Hospital, School of Medicine, Tongji University, Shanghai, China
³Frontiers Science Center for Intelligent Autonomous Systems, Tongji University, Shanghai, China
⁴Collaborative Innovation Center for Brain Science, Tongji University, Shanghai, China
⁵Central Laboratory, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China
⁶School of Mechanical Engineering, Tongji University, Shanghai, China
⁷Shanghai Institute of Thoracic Oncology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
⁸Key Laboratory of Multi-cell Systems, Shanghai Key Laboratory of Molecular Andrology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
⁹Tongji University Cancer Center, Shanghai Tenth People’s Hospital, School of Medicine, Tongji University, Shanghai, China
¹⁰Institute for Regenerative Medicine, Shanghai East Hospital, Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai Key Laboratory of Signaling and Disease Research, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, Chin
¹¹National Key Laboratory of Autonomous Intelligent Unmanned Systems, Tongji University, Shanghai, China
¹²College of Electronics and Information Engineering, Tongji University, Shanghai, China
¹³Center for Biomedical Technology, Universidad Politécnica de Madrid, Pozuelo de Alarcón, Madrid, Spain
¹⁴Department of Neurological Surgery, Lou and Jean Malnati Brain Tumor Institute, Northwestern, University Feinberg School of Medicine, Chicago, IL, USA
¹⁵Key Laboratory of Systems Health Science of Zhejiang Province, School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, Zhejiang, China
^†These authors contributed equally: Yingze Li, Mengge Zheng, Zhenyan Zhu, Yajuan Zhang
Correspondence: ()Weiwei Yang(wyang@sibcb.ac.cn)Yichao Tang(tangyichao@tongji.edu.cn)Haipeng Liu(haipengliu@tongji.edu.cn)Chang Chen(changchenc@tongji.edu.cn)

Mechanical forces are emerging physical cues that regulate biochemical signals of immune cells for antitumor immunity. Owing to the lack of precise tools to impose intracellular forces, little is known about whether and how organelle-level forces trigger mechanotransduction for antitumor immunity. Here, we developed a magneto-mechanical force-triggered lysosomal membrane permeabilization (MagLMP) strategy to induce durable macrophage repolarization for in vivo applications. Self-assembled magnetic nanomotors are driven by rotational magnetic fields, facilitating dynamic damage to the lysosomal membrane by a finely tuned torque-induced vortex. Intriguingly, galectin 9 (Gal9) was found to be critical for sensing cyclic MagLMP, which dynamically activated AMP-activated protein kinase (AMPK), enhanced activation of nuclear factor kappa B (NF-κB), and induced metabolic alterations for sustained M1-like macrophage repolarization, followed by mounting of antitumor immunity. Through single-cell RNA sequencing of tumor tissues, as well as macrophage depletion-reconstitution models involving intratumoral transfer of Gal9-KO bone marrow-derived macrophages (BMDMs) and AMPK shRNA-transduced Gal9-KO BMDMs, we confirmed the Gal9-AMPK-NF-κB axis as the essential pathway by which MagLMP functions in antitumor therapy. In a mouse model of lung adenocarcinoma in situ, overall survival was extended after intravenous administration of nanomotors followed by cyclic MagLMP, and one third of mice survived for more than 300 days. Together, these results demonstrate an intracellular mechanical strategy that can dynamically manipulate innate immune responses in vivo, providing a tool for durable immunotherapy through organelle mechanotransduction.

https://doi.org/10.1038/s41422-025-01217-1

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