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

Table 5 Major resistance mechanisms and possible sensitization approaches

Resistance mechanism	Biological basis	Possible sensitization approach	Ref.
Low mitochondrial respiration/Warburg phenotype	Reduced TCA-cycle activity limits lipoylated substrate abundance and cuproptosis sensitivity	Inhibit glycolysis or shift metabolism toward OXPHOS	[46-51,75-86,269,296-306]
FDX1 downregulation	Reduces Cu2+ reduction and decreases lipoylation-related cuproptosis susceptibility	Restore FDX1 expression or block negative regulators	[87-98,143-146,307-311]
LIAS suppression	Reduces mitochondrial protein lipoylation and limits cuproptosis substrate formation	Restore LIAS expression or combine with OGT/epigenetic modulators	[121,123]
DLAT insufficiency or altered mitochondrial substrate availability	Limits aggregation of lipoylated DLAT and downstream proteotoxic stress	Increase mitochondrial TCA-cycle dependence or select DLAT-high tumors	[42,43,94,235,236]
Copper efflux activation	ATP7A/ATP7B-mediated copper export lowers intracellular copper accumulation	Inhibit copper efflux or enhance tumor copper retention	[66-74,312]
Hypoxia and HIF-1α activation	Promotes glycolysis and reduces mitochondrial respiration-dependent cuproptosis sensitivity	Combine with hypoxia modulation or metabolic reprogramming strategies	[47,245-247,269]
Dense ECM/stromal barriers	Limits penetration of copper ionophores and nanodrugs, especially in PDAC and GC	Use matrix-remodeling delivery systems or stromal-modulating strategies	[249-254,256-258]
Antioxidant buffering/high GSH	Scavenges ROS and weakens copper-dependent oxidative stress	Use GSH-depleting or redox-active nanoplatforms	[206-220,232,290-293,313]
Alternative death pathway dominance	Ferroptosis, apoptosis, ICD, or CDT-induced oxidative injury may coexist with cuproptosis, complicating mechanism attribution	Use pathway-specific inhibitors, copper chelation rescue, FDX1/LIAS/DLAT validation, and lipoylated protein aggregation assays	[62,106,114-118,221-232,312-316]
Systemic copper toxicity	Off-target copper accumulation may injure liver, kidney, brain, or other organs	Develop tumor-selective activation systems and evaluate long-term clearance and organ toxicity	[259-268]

TCA: Tricarboxylic acid cycle; OXPHOS: Oxidative phosphorylation; FDX1: Ferredoxin 1; LIAS: Lipoic acid synthase; OGT: O-GlcNAc transferase; DLAT: Dihydrolipoamide S-acetyltransferase; ATP7A: ATPase copper transporting alpha; ATP7B: ATPase copper transporting beta; HIF-1α: Hypoxia-inducible factor-1α; ECM: Extracellular matrix; PDAC: Pancreatic ductal adenocarcinoma; GC: Gastric cancer; GSH: Glutathione; ROS: Reactive oxygen species; ICD: Immunogenic cell death; CDT: Chemodynamic therapy.