靶向癌症中的金属依赖性细胞死亡：从分子回路到生物标志物指导的精准联合治疗

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.