Researchers at MD Anderson discovered that radiotherapy (RT) triggers cuproptosis—a copper-dependent form of cell death—by raising mitochondrial copper levels through upregulation of the copper transporter CTR1 and depletion of mitochondrial glutathione. In radioresistant tumors, the transcription factor BACH1 is downregulated, which unleashes copper-sequestering proteins called metallothioneins (MT1E/X) that neutralize cuproptosis and confer resistance. Treating radioresistant cancer cells and tumor models with copper ionophores restored sensitivity to RT by enhancing cuproptosis. Clinical evidence from patient esophageal tumors confirmed that RT depletes cuproptosis hallmark proteins in vivo, validating the mechanism and opening a new therapeutic avenue against radioresistant cancers.
