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

  • Cancer Cell. 2025 Jun 9;43(6):1076-1092.e5. doi: 10.1016/j.ccell.2025.03.031.
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
  • 1. Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • 2. Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • 3. Department of Molecular and Cellular Oncology, Division of Basic Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • 4. Department of Thoracic and Cardiovascular Surgery, Division of Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • 5. Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • 6. Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX 77030, USA.
  • 7. Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: [email protected].
  • 8. Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX 77030, USA. Electronic address: [email protected].
PMID: 40215978 DOI: 10.1016/j.ccell.2025.03.031
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.
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