Regulating copper homeostasis of tumor cells to promote cuproptosis for enhancing breast cancer immunotherapy

Meng Guan, Kai Cheng, Xiao-Ting Xie, Yong Li, Meng-Wen Ma, Bin Zhang, Si Chen, Wei Chen, Bo Liu (), Jin-Xuan Fan () and Yuan-Di Zhao ()
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Meng Guan: Huazhong University of Science and Technology
Kai Cheng: Huazhong University of Science and Technology
Xiao-Ting Xie: Huazhong University of Science and Technology
Yong Li: Huazhong University of Science and Technology
Meng-Wen Ma: Huazhong University of Science and Technology
Bin Zhang: Huazhong University of Science and Technology
Si Chen: Wuhan Institute of Technology
Wei Chen: Huazhong University of Science and Technology
Bo Liu: Huazhong University of Science and Technology
Jin-Xuan Fan: Huazhong University of Science and Technology
Yuan-Di Zhao: Huazhong University of Science and Technology

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: Abstract Cuproptosis is an emerging mode of programmed cell death for tumor suppression but sometimes gets resisted by tumor cells resist under specific mechanisms. Inhibiting copper transporter ATPase (ATP7A) was found to disrupt copper ion homeostasis, thereby enhancing the effect of cuproptosis and eventually inhibiting tumor invasion and metastasis. In this study, we develop a multifunctional nanoplatfrom based on Cu9S8 (CAPSH), designed to enhance cuproptosis in tumor cells by specifically targeting ATP7A interference, while combining thermodynamic therapy with immune effects. The release of copper ions from CAPSH and the copper homeostasis interference by siRNA cooperatively increases the concentration of copper ions in tumor cells, which induces effectively cuproptosis and activates immune responses for suppressing development and metastasis of tumor. This nanoplatform simultaneously regulates cuproptosis from both principles of onset and development, facilitating the application of cuproptosis in tumor therapy.

Date: 2024
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DOI: 10.1038/s41467-024-54469-7

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