Citation: Xinlu Zhang, Yongxin Liu, Huan Li, Shutong Chen, Guocheng Wang, Xu Zhang, Chen Cao, Xiaoyuan Chen, Sheng Wang. A hypoxia-activated copper ion nanoexchanger for cancer immunotherapy by in situ precise production of immunogenic cell death inducer[J]. Chinese Chemical Letters, ;2026, 37(3): 111404. doi: 10.1016/j.cclet.2025.111404 shu

A hypoxia-activated copper ion nanoexchanger for cancer immunotherapy by in situ precise production of immunogenic cell death inducer

Xinlu Zhang ^a ,
Yongxin Liu ^a ,
Huan Li ^a ,
Shutong Chen ^a ,
Guocheng Wang ^a ,
Xu Zhang ^a ,
Chen Cao ^a ,
Xiaoyuan Chen ^{b, c, d, e, f, g, h, i, *,} ,
Sheng Wang ^{a, *,}

a.
School of Life Sciences, Faculty of Medicine, Tianjin University, Tianjin 300072, China
b.
Department of Diagnostic Radiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119074, Singapore
c.
Department of Chemical and Biomolecular Engineering, College of Design and Engineering, National University of Singapore, Singapore 117575, Singapore
d.
Department of Biomedical Engineering, College of Design and Engineering, National University of Singapore, Singapore 117575, Singapore
e.
Department of Pharmacy and Pharmaceutical Sciences, Faculty of Science, National University of Singapore, Singapore 117544, Singapore
f.
Clinical Imaging Research Centre, Centre for Translational Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117599, Singapore
g.
Nanomedicine Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore
h.
Theranostics Center of Excellence (TCE), Yong Loo Lin School of Medicine, National University of Singapore, Singapore 138667, Singapore
i.
Institute of Molecular and Cell Biology, Agency for Science, Technology, and Research (A*STAR), Singapore 138673, Singapore

chen.shawn@nus.edu.sg

shengwang@tju.edu.cn

Received Date: 18 March 2025
Revised Date: 30 May 2025
Accepted Date: 3 June 2025
Available Online: 3 June 2025

Figures(4)

In situ therapeutic agent production strategy is promising to overcome the drawbacks of direct drug delivery. Hypoxia provides a great target for precise treatment of tumor. Here we report a copper ion competition-based nanoparticle (NP) for hypoxia-activated formation of diethyldithiocarbamate (DTC)-copper complex, an immunogenic cell death (ICD) inducer. The NP is composed of an amphiphilic hypoxia-responsive DTC precursor and a fluorescence quenched copper ion-chelated squaric acid. In hypoxic tumor cells, the azobenzene linker in DTC precursor can be cleaved through bioreduction, leading to DTC release and subsequent copper ion exchange between DTC and squaric acid. Simultaneous formation of toxic DTC-copper complexes and fluorescence recovery will allow for visualization of in situ therapeutic agents production. Furthermore, the DTC-copper complexes can induce ICD and promote cytotoxic T lymphocyte infiltration for cancer immunotherapy. This study not only provides a promising hypoxia-activated nanomedicine for precision cancer therapy, but also a visualization strategy for evaluating the treatment process.
- Precise therapy,
- Hypoxia-responsive prodrug,
- Immunotherapy,
- Copper,
- Reactive oxygen species
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