Radiotherapy Promotes Cuproptosis and Synergizes With Cuproptosis Inducers To Overcome Tumor Radioresistance

Authors

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

Publication Date

6-9-2025

Journal

Cancer Cell

DOI

10.1016/j.ccell.2025.03.031

PMID

40215978

PMCID

PMC12151758

PubMedCentral® Posted Date

6-9-2026

PubMedCentral® Full Text Version

Post-print

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

Humans, Radiation Tolerance, Animals, Copper, Mice, Cell Line, Tumor, Esophageal Neoplasms, Mitochondria, Copper Transporter 1, Xenograft Model Antitumor Assays, Ferroptosis, Apoptosis, Metallothionein, Gene Expression Regulation, Neoplastic, Glutathione, Female, copper, cuproptosis, metallothionein, radioresistance, radiotherapy

Published Open-Access

yes

Recommended Citation

Lei, Guang; Sun, Mingchuang; Cheng, Jun; et al., "Radiotherapy Promotes Cuproptosis and Synergizes With Cuproptosis Inducers To Overcome Tumor Radioresistance" (2025). Faculty, Staff and Student Publications. 5178.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/5178