Targeting Metal-Dependent Cell Death in Cancer: From Molecular Circuitry to Biomarker-Guided Precision Combination Therapy.

Cuproptosis and ferroptosis are increasingly recognised not merely as parallel metal-dependent regulated cell death programmes, but as dynamic state variables of tumour metabolism, redox buffering and immune contexture. In this review, we synthesise the field beyond a descriptive pathway summary. We first integrate the core circuitry that governs death susceptibility, including copper trafficking, mitochondrial protein lipoylation and oxidative phosphorylation, iron handling, polyunsaturated-lipid remodelling, and the glutathione-GPX4/FSP1 antioxidant network. We then critically examine pan-cancer and multi-omics signatures, arguing that transcriptomic scores alone are insufficient to define therapeutic vulnerability without functional state readouts. Preclinical evidence is next reorganised around clinically relevant tasks - reversing drug persistence, radiosensitising resistant tumours, converting immune-cold lesions, and extending opportunities in rare, refractory and paediatric cancers - rather than around pathway labels alone. Particular emphasis is placed on the mechanistic crosstalk between cuproptosis and ferroptosis, the immune consequences of metal-dependent death such as cGAS-STING activation and myeloid remodelling, and the emerging logic of combining metal-death induction with radiotherapy, chemotherapy, immune checkpoint blockade and cellular immunotherapies. Finally, we propose a biomarker-guided translational framework that distinguishes cuproptosis-prone, ferroptosis-prone and state-switching tumours, outlines clinically accessible biomarkers and pharmacodynamic readouts, and positions schedule design, delivery selectivity and systemic-to-tumour toxicity separation as central determinants of success. This perspective reframes metal-dependent cell death from descriptive biology into a deployable precision-oncology strategy.