Discovery of Cu(II)‐Dipyridophenazine Complex for Synergistic Cuproptosis/Chemodynamic Therapy via Disrupting the Tricarboxylic Acid (TCA) Cycle in Metastatic TNBC

Cuproptosis, a recently recognized regulated cell death, distinct from established death mechanisms, offers promising cancer therapy. However, its efficacy relies on intracellular copper availability and homeostasis. Herein, a novel Copper(II) dipyridohenazine complex, Cu(L¹)₂Cl acts as an oxidative stress amplifier and glutathione (GSH) disrupter for synergistic cuproptosis/chemodynamic anticancer therapy for the treatment of challenging triple negative breast cancer. Cu(L¹)₂Cl followed the endocytosis pathway to enter tumor cells and depleted GSH to release Cu⁺ ions which result in the production of^.OH radicals generated from H₂O₂, leading to chemodynamic therapy. The spike in ROS generation disrupts cellular redox homeostasis, causing impaired mitochondrial function, ATP depletion, and endoplasmic reticulum stress generation. ATP depletion directly affects the function of copper-transporting ATPase 1 (ATP7A), resulting in a large amount of Cu⁺ trapped inside cancer cells, causing oligomerization of dihydrolipoamide S-acetyltransferase (DLAT), and depletion of Lipoyl synthase (LIAS), and leading to cellular cuproptosis. Subsequently, Cu(L¹)₂Cl interrupts tumor metastasis and evokes immunogenic cell death (ICD) by promoting high mobility group protein (HMGB1), ATP and lactate dehydrogenase (LDH) release, calreticulin (CRT) exposure, and inhibiting programmed death ligand 1 (PD-L1). The in vivo studies on 4T1 tumor bearing Balb/c mice validate its potent antitumor efficacy, thereby providing a new therapeutic paradigm to augment cuproptosis-related therapies.