Copper homeostasis imbalance and cuproptosis: Emerging targets and strategies for gastrointestinal tumor therapy

Gastrointestinal malignancies, including gastric, colorectal, and pancreatic cancers, are characterized by metabolic reprogramming, multidrug resistance, and immunosuppressive microenvironments that limit clinical outcomes. Cuproptosis is a mitochondrial respiration-dependent form of regulated cell death that may target the “cuproplasia” phenotype of gastrointestinal tumors. Mechanistically, ferredoxin 1-mediated reduction of Cu2+ to Cu+ promotes toxic aggregation of lipoylated tricarboxylic acid cycle proteins, including dihydrolipoamide S-acetyltransferase, and destabilizes iron-sulfur clusters. Therapeutic disruption of copper homeostasis may therefore induce irreversible proteotoxic stress by altering the balance between glycolysis and oxidative phosphorylation. This review summarizes mechanisms of copper homeostasis imbalance and cuproptosis in gastrointestinal malignancies and discusses emerging interventions, including synthetic copper ionophores, traditional Chinese medicine phytochemicals, modulation of the dietary copper-gut microbiota axis, and stimuli-responsive nanomedicine. We further highlight nanomedicine-enabled stromal barrier penetration, magnetic resonance imaging/positron emission tomography-guided theranostics, immunogenic cell death-mediated synergy with immunotherapy, and translational challenges involving ferredoxin 1-based patient stratification and safety window management.