Metal-Dependent Cell Death Networks Under Therapeutic Pressure: Ferroptosis-Cuproptosis Crosstalk in Drug-Resistant Cancer
DOI:
https://doi.org/10.66505/cbtt.v1i2.34Keywords:
ferroptosis, cuproptosis, therapy resistance, cancer therapeutics, metabolic reprogramming, tumor microenvironment, metabolic plasticityAbstract
Therapy resistance remains a principal cause of cancer relapse and mortality, reflecting the ability of tumor cells to remodel metabolic, redox, and stress-adaptation networks under therapeutic pressure. Ferroptosis is executed by iron-driven peroxidation of polyunsaturated phospholipids, whereas cuproptosis arises from copper-triggered mitochondrial proteotoxic stress centered on lipoylated TCA cycle proteins and Fe-S cluster disruption. Although mechanistically distinct, these programs converge through shared transition-metal redox chemistry, mitochondrial metabolism, and metabolic plasticity. Drug-selected tumor states frequently acquire a dual-shielded phenotype that couples reinforced antioxidant buffering, exemplified by NRF2 activation and SLC7A11-GSH-GPX4 maintenance, with copper-trafficking adaptations, such as upregulation of ATP7A and ATP7B and enhanced copper sequestration, thereby suppressing both lipid peroxidation and copper-induced proteotoxicity. This integrated view highlights metabolic state as a gatekeeper, with OXPHOS dependence, lipoylation capacity, and metal transport profiles shaping sensitivity windows and informing biomarker-guided stratification. We discuss actionable nodes across iron and copper handling, redox defense, and mitochondrial metabolism, and outline combination strategies that pair ferroptosis inducers with copper ionophores or copper chelators, integrate metabolic interventions, and leverage nanotechnology-enabled delivery to improve selectivity. Together, these findings support a unified model in which metal-dependent death pathways represent exploitable vulnerabilities in therapy-resistant tumors and provide a mechanistic foundation for rational resensitization strategies.
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National Natural Science Foundation of China
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