Cuproptosis, a recently defined copper-dependent cell death, remains largely unexplored in tumor therapies, particularly in breast cancer. Our study demonstrates that triple-negative breast cancer (TNBC) bears a relative elevated copper levels and exhibit resistance to cuproptosis. Mechanistically, cooper activates AKT1 signaling pathway, which inhibits cuproptosis by directly phosphorylating ferredoxin-1 (FDX1), a key regulator involved in cuproptosis. AKT1-mediated FDX1 phosphorylation abrogates FDX1-induced cuproptosis and aerobic respiration, accompanied by promoting glycolysis. Consequently, combination of AKT1 inhibitors MK2206 and the copper ionophore elesclomol (ES) synergistically inhibits TNBC tumorigenesis both in vitro and in vivo. In summary, our findings uncover a critical mechanism underlying TNBC resistance to cuproptosis and propose a potential therapeutic approach for TNBC.