Cuproptosis in gastric cancer: Mechanisms and therapeutic opportunities

Table 1 Representative agents/platforms and proposed mechanisms

Strategy	Representative agents/platforms and evidence	Proposed mechanism
Copper ionophores	Elesclomol; disulfiram/copper (DSF/Cu); cisplatin plus disulfiram for advanced gastric cancer (NCT05667415; not yet recruiting; no results posted)[83-86]	Increase intracellular copper, promote mitochondrial stress, induce cuproptosis-related or ROS-dependent cytotoxicity, and enhance chemotherapy response[31,61,83,84,86]
Copper chelators	Tetrathiomolybdate, D-penicillamine, triethylenetetramine/tetraethylenepentamine[87-89]	Reduce copper bioavailability, inhibit copper-driven angiogenesis, and may modulate immune checkpoint signaling and tumor vascularization[16,87-89]
Copper-based or copper-modulating nanomedicine	CuO nanoparticles, elesclomol-loaded copper oxide nanoplatforms, CuMoO4-based systems, mitochondria-targeted copper-depleting nanoparticles[90-96]	Improve tumor-targeted copper delivery or depletion, induce mitochondrial stress/cuproptosis, and enable combination with photothermal therapy, chemotherapy, or immunotherapy[90-96]
Combination therapy	Copper modulation plus chemotherapy, immune checkpoint blockade, targeted therapy, or photothermal therapy[17,88,90,94,95]	May overcome drug resistance, reshape the tumor microenvironment, and convert immunologically cold tumors into more responsive phenotypes[17,88,90,93,95]

Copper-modulating therapeutic strategies and translational challenges in gastric cancer. ROS: Reactive oxygen species.

Table 2 Evidence level and translational limitations

Strategy	Current evidence level	Main limitations
Copper ionophores	Gastric cancer-specific preclinical evidence; registered disulfiram/cisplatin gastric cancer trial is exploratory and has no posted results[61,85,86,90,97]	Narrow window, systemic toxicity, unclear patient selection, no mature gastric cancer efficacy data, and context-dependent mitochondrial metabolism[84-86]
Copper chelators	Mostly preclinical or early clinical evidence in non-GC malignancies; direct GC-specific clinical evidence remains limited[87,88]	Non-selective systemic copper depletion, potential neurological/hematological toxicity, and uncertain optimal combination schedules[87-89]
Copper-based or copper-modulating nanomedicine	Predominantly preclinical evidence in tumor models, with limited gastric cancer-specific validation[90-96]	Biodistribution, long-term safety, manufacturing reproducibility, and regulatory translation remain unresolved[89,91,93,95]
Combination therapy	Strong mechanistic rationale, but prospective biomarker-guided gastric cancer trials are still needed; clinical exploration remains limited[85,86,95]	Requires validated biomarkers, toxicity monitoring, dose optimization, and careful sequencing of treatment modalities[86,88,95]

Copper-modulating therapeutic strategies and translational challenges in gastric cancer. GC: Gastric cancer.

Table 3 Biological roles

Pathway/biomarker	Role in copper metabolism or cuproptosis
FDX1	Reduces Cu2+ to Cu+ and promotes lipoylation-dependent aggregation of TCA-cycle proteins, especially DLAT[31-33,97,122]
DLAT/LIAS/LIPT1/DLD (lipoylation-related genes)	Core components of mitochondrial protein lipoylation and lipoylated TCA-cycle protein aggregation during cuproptosis[31,34,43,47]
SLC31A1/ATP7A/ATP7B (copper transporters)	Regulate copper uptake and efflux; ATP7A/ATP7B can also influence platinum-drug transport and chemoresistance[11,16,30,52-56]
AOC1	Copper-containing amine oxidase involved in polyamine catabolism and ROS-related metabolic stress[123,124]
ITGB1	Integrin-mediated regulator of cell adhesion, metabolism, migration, and cuproptosis-related phenotypes[125,126]
SERPINE1	Regulates extracellular matrix remodeling, EMT, angiogenesis, apoptosis, and immune infiltration[127-130]

Cuproptosis-related pathways and candidate biomarkers in gastric cancer. FDX1: Ferredoxin 1; TCA: Tricarboxylic acid; DLAT: Dihydrolipoamide S-acetyltransferase; LIAS: Lipoic acid synthetase; LIPT1: Lipoyltransferase 1; DLD: Dihydrolipoamide dehydrogenase; ATP7A/ATP7B: ATPase copper-transporting alpha/bet; SLC31A1: Solute carrier family 31 member 1; AOC1: Amine oxidase copper-containing 1; ROS: Reactive oxygen species; EMT: Epithelial-mesenchymal transition; SERPINE1: Serpin family E member 1; ITGB1: Integrin β1.

Table 4 Gastric cancer evidence and clinical implications

Pathway/biomarker	Evidence in gastric cancer	Potential clinical implication
FDX1	Linked to cuproptosis sensitivity, copper-lactylation signaling, and immune infiltration in gastric cancer-related studies[97,121,122,131,132]	Candidate marker for cuproptosis susceptibility and rational selection of copper-modulating strategies[97,121,122,131,132]
DLAT/LIAS/LIPT1/DLD (lipoylation-related genes)	Altered expression of lipoylation-related genes has been associated with gastric cancer metabolism and prognosis[47,49-50,122]	May help define tumors with mitochondrial metabolic dependence and potential vulnerability to cuproptosis induction[31,47,122]
SLC31A1/ATP7A/ATP7B (copper transporters)	Copper transporter dysregulation may affect intracellular copper accumulation, angiogenesis, and response to platinum-based therapy[16,52-56]	Potential targets to enhance copper-mediated cytotoxicity or overcome chemotherapy resistance[52-56]
AOC1	AOC1 down-regulation suppresses AKT signaling, epithelial-mesenchymal transition, proliferation, invasion, and migration in gastric cancer cells[124]	Candidate therapeutic and prognostic biomarker linked to tumor growth and metastasis[124]
ITGB1	High ITGB1 expression is associated with poor prognosis in diffuse gastric cancer and may reduce sensitivity to copper ionophores[125,126]	Potential stratification marker and actionable node for enhancing cuproptosis-based therapy[125,126]
SERPINE1	Elevated SERPINE1 expression in gastric adenocarcinoma is associated with proliferation, migration, and immunosuppressive features[128-130]	Candidate prognostic and immune-related marker that may guide combination strategies[128-130]

Cuproptosis-related pathways and candidate biomarkers in gastric cancer. FDX1: Ferredoxin 1; DLAT: Dihydrolipoamide S-acetyltransferase; LIAS: Lipoic acid synthetase; LIPT1: Lipoyltransferase 1; DLD: Dihydrolipoamide dehydrogenase; ATP7A/ATP7B: ATPase copper-transporting alpha/bet; SLC31A1: Solute carrier family 31 member 1; AOC1: Amine oxidase copper-containing 1; SERPINE1: Serpin family E member 1; ITGB1: Integrin β1.