GPX1 drives cuproptosis-ferroptosis resistance in cold tumors.

Cold tumors, defined by an immunosuppressive microenvironment and metabolic stress, including glutamine deficiency, frequently exhibit resistance to therapeutic interventions. This study examined the role of glutathione peroxidase 1 (GPX1) in mediating resistance to cuproptosis and ferroptosis during glutamine deprivation. Through integrated multi-omics analyses, CRISPR-mediated gene editing, and functional assays in cold tumor cell lines, we identified GPX1 as a key regulator of redox homeostasis and a protector against cuproptosis. Upstream, glutamine deprivation induced the SLC7A11 upregulation, which enhanced GPX1-mediated resistance through the maintenance of pyrimidine metabolism. Downstream, GPX1 knockout mediated cross-sensitization to ferroptosis by altering the Fenton reaction, thereby exacerbating cell death. In vivo experiments confirmed that GPX1 knockout restored sensitivity to cuproptosis inducers and improved the efficacy of PD-L1 blockade. Collectively, these findings position GPX1 as a central metabolic checkpoint in cold tumors and highlight the SLC7A11-UMPs-GPX1 axis as a promising therapeutic target for overcoming treatment resistance and enhancing immunotherapy response.