2. Academic Validation
  3. Radiotherapy promotes cuproptosis and synergizes with cuproptosis inducers to overcome tumor radioresistance

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

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: shlin@mdanderson.org.
  • 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: bgan@mdanderson.org.
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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