Copper promotes breast cancer through immunometabolic reprogramming: a multi-omics mediation analysis

BACKGROUND: Elevated copper concentration or Cu/Zn ratio have been consistently observed in the blood and tumor tissues of breast cancer patients, while the underlying mechanisms remain unclear. The objective of this study was to assess the effects of plasma Cu on breast cancer risk and the associated immunometabolic pathways. METHODS: We conducted a nested case-control study (226 matched pairs) within the Taizhou Longitudinal Study. Plasma levels of Cu and Zn were quantified, and large-scale proteomic and metabolomic profiling was performed. Structural equation modeling (SEM) and network toxicology analyses were applied to explore Cu-associated immunometabolic pathways. RESULTS: Higher plasma Cu was significantly associated with increased breast cancer risk (adjusted OR=1.29, 95% CI: 1.04-1.61). Proteomic analyses identified two Cu-related inflammatory proteins, CCL23 and HGF, significantly linked to breast cancer. The metabolites associated with breast cancer, HGF and CCL23 were enriched in alanine, aspartate, and glutamate metabolism. Structural equation modeling revealed two Cu-driven immunometabolic axes: (i) Cu→CCL23→succinate/NAAG and (ii) Cu→HGF→NAAG, mediating approximately 30% of Cu's effect on breast cancer risk. Functional enrichment of succinate-related genes implicated apoptosis, mitochondrial regulation, and MAPK/JAK-STAT signaling. NAAG-related genes were enriched in proteolytic activity, focal adhesion, and actin cytoskeleton remodeling pathways, indicating roles in tumor progression. CONCLUSIONS: Our findings reveal novel Cu-driven immunometabolic pathways mediating breast cancer risk through inflammation-metabolism crosstalk. These insights highlight potential targets for prevention and intervention in Cu-associated breast carcinogenesis. IMPACT: Findings in this study highlight potential targets for prevention and intervention in Cu-associated breast carcinogenesis.