Targeting Metal-Dependent Cell Death in Cancer: From Molecular Circuitry to Biomarker-Guided Precision Combination Therapy.
This review integrates cuproptosis and ferroptosis circuitry, immune effects, preclinical combination strategies, and proposed biomarkers into a precision-oncology framework that includes potential applications in rare, refractory, and pediatric cancers.
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This review integrates cuproptosis and ferroptosis circuitry, immune effects, preclinical combination strategies, and proposed biomarkers into a precision-oncology framework that includes potential applications in rare, refractory, and pediatric cancers.
Research significance
The supplied record supports mechanistic and preclinical rationale for biomarker-guided induction of cuproptosis or ferroptosis in combination with radiotherapy, chemotherapy, checkpoint blockade, or cellular immunotherapy; it remains an inference—not demonstrated pediatric clinical evidence—that functional state profiling and selective delivery could improve responses in resistant pediatric tumors.
Source abstract
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.