ATP7A-mediated copper ion efflux reprogrammes tumour immunity and promotes cisplatin resistance in cervical cancer.

Cisplatin resistance is a major obstacle to effective chemotherapy in patients with cervical cancer and is associated with an immunosuppressive tumour microenvironment. Copper ions are essential trace elements that regulate redox and immune balance. However, the connections among copper ions, cisplatin resistance and immune regulation remain unclear. Here, higher serum copper levels correlated with increased pan-cancer mortality. Integrative transcriptomic and single-cell RNA sequencing analyses revealed lower copper-related transcriptional activity in CD8⁺ T cells from cervical cancer tissues. Multiomics analysis revealed that ATPase copper transporting alpha (ATP7A) expression was upregulated in cisplatin-resistant patients compared with sensitive patients and correlated with poor survival. ATP7A knockdown increased sensitivity to cisplatin and promoted cuproptosis, whereas ATP7A overexpression increased cisplatin resistance and impaired CD8⁺ T cells through copper ion efflux. Furthermore, excess copper ions directly bind to the lymphocyte-specific protein tyrosine kinase (LCK) activation loop (Tyr394), impairing T-cell receptor (TCR) signalling in CD8⁺ T cells. Sex-determining region Y-box 21 (SOX21) directly binds two conserved motifs within the ATP7A promoter (-372 bp and -245 bp) and enhances its transcriptional activity. These results revealed a SOX21/ATP7A/copper ion axis connecting copper ion efflux with immune suppression and cisplatin resistance. Targeting ATP7A or copper ion efflux may restore CD8⁺T-cell activity and enhance the efficacy of cisplatin for the treatment of cervical cancer.