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

Table 4 Therapeutic strategies targeting cuproptosis and their evidence level

Strategy	Representative mechanism	Current evidence level	Main limitation	Ref.
Copper ionophores	Increase intracellular copper and induce mitochondrial copper toxicity	Mainly preclinical tumor models	Systemic toxicity, delivery instability, and patient selection remain unresolved	[119,120,122-127]
Disulfiram/CuET-based therapy	Forms cytotoxic copper complexes and induces oxidative/mitochondrial stress	Preclinical and organoid evidence	Stability, specificity, and mechanism heterogeneity	[128-134]
FDX1-LIAS-DLAT axis modulation	Enhances lipoylated substrate availability and copper sensitivity	Preclinical mechanistic evidence	Requires validated biomarkers and rescue experiments	[92-98,137-146]
Metabolic sensitization	Shifts tumor cells from glycolysis toward OXPHOS to increase cuproptosis susceptibility	Preclinical evidence	Tumor metabolic states are heterogeneous and context-dependent	[47,50,140,269]
Chemotherapy sensitization	Combines copper stress with platinum drugs, 5-FU, gemcitabine, or metabolic stress	Preclinical evidence in GC, CRC, and PDAC models	Optimal tumor subtype and treatment sequence remain unclear	[147-150]
Immunotherapy combination	Cuproptosis-associated mitochondrial stress may enhance cGAS-STING activation, ICD-like responses, and immune checkpoint blockade	Preclinical evidence	Immune activation is context-dependent and should not be considered the defining mechanism of cuproptosis	[151-160,287,288]
TME-responsive nanomedicine	pH/GSH/H2O2-triggered copper release, ROS amplification, and mitochondrial injury	Preclinical nanoplatform studies	Platform complexity, biodistribution, clearance, and reproducibility	[203-220,289-293]
PTT/PDT/CDT-enhanced cuproptosis	Uses external energy and redox cycling to enhance ROS production, copper release, and cuproptosis-related cytotoxicity	Preclinical nanomedicine evidence	Difficult to distinguish cuproptosis from CDT/PDT/PTT-induced nonspecific oxidative injury	[227,230-232]
Theranostic platforms	Imaging-guided copper delivery and response monitoring	Preclinical imaging studies	Imaging signal does not directly prove cuproptosis activation	[255,270-277,279-286,294,295]

CuET: Copper diethyldithiocarbamate; FDX1: Ferredoxin 1; LIAS: Lipoic acid synthase; DLAT: Dihydrolipoamide S-acetyltransferase; OXPHOS: Oxidative phosphorylation; GC: Gastric cancer; CRC: Colorectal cancer; PDAC: Pancreatic ductal adenocarcinoma; cGAS: Cyclic GMP-AMP synthase; STING: Stimulator of interferon genes; ICD: Immunogenic cell death; TME: Tumor microenvironment; GSH: Glutathione; ROS: Reactive oxygen species; PTT: Photothermal therapy; PDT: Photodynamic therapy; CDT: Chemodynamic therapy.