Molin Liu, Jian Zheng, M. Y. Yu, Qirui Wang, Yi Yuan, Nannan Shao, Xiaoliang Yang, Tianxi Shen, Li Wang, Aiyun Li, Rui Liu, Ji‐Min Cao, Xi Liu, Fangfang Cao, Yanlin Feng
Abstract Triple‐negative breast cancer (TNBC) exhibits high copper and iron uptake, making cuproptosis and ferroptosis promising therapeutic strategies. However, their efficacy is limited by TNBC's intrinsic antioxidant defences. Herein, CuFeTe 2 nanosheets (CFT) with internal tumour microenvironment (TME) responsiveness and external NIR‐II mild photothermal enhancement is developed to synergistically overcome this antioxidant defences, amplifying both pathways for improved TNBC therapy. In the acidic TME, CFT releases Fe 2+ and Cu 2+ . Cu 2+ reacted with glutathione (GSH) to generate Cu + , inhibiting glutathione peroxidase 4 (GPX4), amplifying lipid peroxidation (LPO), and triggering ferroptosis. Cu⁺ also induce dihydrolipoamide S‐acetyltransferase (DLAT) aggregation and disrupts iron‐sulfur (Fe–S) cluster proteins, initiating cuproptosis. Meanwhile, Fe 2+ overload further reinforced ferroptosis. Both Fe 2+ and Cu + catalyze H 2 O 2 decomposition into hydroxyl radicals (•OH), while NIR‐II photothermal effects accelerated this process, intensifying oxidative stress and ferroptosis. Moreover, ferroptosis depleted heat shock protein 70 (HSP70) and reduces ATP levels, sensitizing tumor cells to cuproptosis. The synergistic activation of ferroptosis and cuproptosis ultimately induced immunogenic cell death (ICD) and a potent immune response. Biodegraded CFT is efficiently excreted via renal filtration, ensuring high biocompatibility and safe clearance. This study presents a TME‐responsive, photothermal‐enhanced nanoplatform that effectively integrates ferroptosis and cuproptosis for potent antitumor therapy.