Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2025 Jun 9;43(6):1076-1092.e5.
doi: 10.1016/j.ccell.2025.03.031. Epub 2025 Apr 10.

Radiotherapy promotes cuproptosis and synergizes with cuproptosis inducers to overcome tumor radioresistance

Guang Lei  1 , Mingchuang Sun  1 , Jun Cheng  1 , Rui Ye  2 , Zhengze Lu  1 , Amber Horbath  1 , David Huo  1 , Shengrong Wu  1 , Anagha Alapati  1 , Sadhna Aggarwal  2 , Zhihao Xu  1 , Chao Mao  1 , Yuelong Yan  1 , Jun Yao  3 , Qidong Li  1 , Xiong Chen  1 , Hyemin Lee  1 , Li Zhuang  1 , Dadi Jiang  2 , Apar Pataer  4 , Jack A Roth  4 , Nicholas Navin  5 , Albert C Koong  2 , Mingjian James You  6 , Steven H Lin  7 , Boyi Gan  8
Affiliations

Radiotherapy promotes cuproptosis and synergizes with cuproptosis inducers to overcome tumor radioresistance

Guang Lei et al. Cancer Cell. .

Abstract

Cuproptosis is a recently identified form of copper-dependent cell death. Here, we reveal that radiotherapy (RT) induces cuproptosis in cancer cells, independent of apoptosis and ferroptosis, and depletes lipoylated proteins and iron-sulfur (Fe-S) cluster proteins-both hallmarks of cuproptosis-in patient tumors. Mechanistically, RT elevates mitochondrial copper levels by upregulating copper transporter 1 (CTR1) and depleting mitochondrial glutathione, a copper chelator, thereby triggering cuproptosis. Integrated analyses of RNA sequencing (RNA-seq) from radioresistant esophageal cancer cells and single-cell RNA-seq from esophageal tumors of patients unresponsive to RT link radioresistance to the downregulation of BTB and CNC homology 1 (BACH1). This downregulation de-represses the expression of copper-sequestering metallothionein (MT) 1E/X, thereby mitigating cuproptosis and contributing to radioresistance. Copper ionophore treatment sensitizes radioresistant cancer cells and cell line- and patient-derived xenografts to RT by potentiating cuproptosis. Our findings unveil a link between RT and cuproptosis and inform a therapeutic strategy to overcome tumor radioresistance by targeting cuproptosis.

Keywords: copper; cuproptosis; metallothionein; radioresistance; radiotherapy.

PubMed Disclaimer

Conflict of interest statement

Declaration of interests B.G., G.L., and J.C. have filed a patent for the use of cuproptosis inducers to overcome radioresistance in cancer treatment.

References

    1. Jaffray DA, Knaul F, Baumann M, and Gospodarowicz M (2023). Harnessing progress in radiotherapy for global cancer control. Nat Cancer 4, 1228–1238. 10.1038/s43018-023-00619-7. - DOI - PubMed
    1. Petroni G, Cantley LC, Santambrogio L, Formenti SC, and Galluzzi L (2022). Radiotherapy as a tool to elicit clinically actionable signalling pathways in cancer. Nat Rev Clin Oncol 19, 114–131. 10.1038/s41571-021-00579-w. - DOI - PMC - PubMed
    1. Adjemian S, Oltean T, Martens S, Wiernicki B, Goossens V, Vanden Berghe T, Cappe B, Ladik M, Riquet FB, Heyndrickx L, et al. (2020). Ionizing radiation results in a mixture of cellular outcomes including mitotic catastrophe, senescence, methuosis, and iron-dependent cell death. Cell Death Dis 11, 1003. 10.1038/s41419-020-03209-y. - DOI - PMC - PubMed
    1. Price JM, Prabhakaran A, and West CML (2023). Predicting tumour radiosensitivity to deliver precision radiotherapy. Nat Rev Clin Oncol 20, 83–98. 10.1038/s41571-022-00709-y. - DOI - PubMed
    1. Schaue D, and McBride WH (2015). Opportunities and challenges of radiotherapy for treating cancer. Nat Rev Clin Oncol 12, 527–540. 10.1038/nrclinonc.2015.120. - DOI - PMC - PubMed

MeSH terms

LinkOut - more resources