The Pharmacological Induction of Cuproptosis: A Novel Strategy for Targeting Drug-Resistant Cancers

Cuproptosis represents a paradigm shift in cancer cell death biology, offering a new therapeutic avenue to overcome multidrug resistance by satisfying basic metabolic requirements, including mitochondrial oxidative phosphorylation and tricarboxylic acid (TCA) metabolism, which are retained even in clinically relevant cancer settings. In contrast to traditional cell death pathways (apoptosis, autophagy, ferroptosis, pyroptosis) cuproptosis is a copper-dependent process in which the Cu 2+ ions directly interact with lipoylated residues of TCA cycle enzymes (especially DLAT and other lipoamidated proteins), leading to protein aggregation, mitochondrial dysfunction, and p53/caspases/BAX/BAK independent immunogenic cell death. Copper ionophores (elesclomol, disulfiram), copper complexes, and nanoparticle-based delivery systems (copper oxide nanoparticles, polydopamine-conjugated carriers, metal-organic frameworks) are pharmacological agents with strong anti-tumor activity in preclinical models and in early clinical trials in cancer biomarkers of drug-resistance, such as triple-negative breast cancer, platinum-resistant ovarian cancer, and hepatocellular carcinoma. The selection of patient stratification key biomarkers (CTR1, FDX1, DLAT expression, and intratumoral copper content) enables the selection of a particular treatment, and the combination approaches with standard chemotherapy, ferroptosis induction, and immunotherapy with checkpoint inhibitors lead to a further increase in treatment efficacy. Although there is positive preclinical and early clinical data, clinical translation of cuproptosis has been highly challenged by several challenges such as narrow therapeutic ranges of copper toxicity, tumor heterogeneity in cuproptosis sensitivity, and development of adaptive resistance; further biomarker identification, nano formulations, combination regimen systematics and mechanistic understanding of resistance mechanisms are essential priorities to develop cuproptosis-based therapies as a transformative element of precision oncology in the treatment-refractory malignancies.