Cu⁺/Ca²⁺ Dual‐Overload Strategy Assisted by Metabolic‐Symbiotic‐Destruction for Tumor Apoptosis and Tumor Immune Activation

Abstract Ion interference including copper (Cu⁺)/calcium (Ca²⁺) overload activate cell‐specific death channels, damage mitochondria and disrupt cellular homeostasis, showing great potential in anti‐tumor therapy. However, the complex metabolic environment and the powerful self‐protection of tumors cause clinical failure of ion interference. Thus, metabolic disruption is expected an innovative strategy for the enhancement of ion interference. Herein, CuS‐α‐CHCA&penthiopyrad@CaCO₃‐RGD nanoparticles (CCPCR NPs) are prepared to provide a Cu⁺/Ca²⁺ dual‐overload anti‐tumor therapy assisted by metabolic‐symbiosis‐destruction strategy, realizing the collapse of tumor self‐protection. Specifically, precise CuS and CaCO₃ delivery triggered irreversible Cu⁺/Ca²⁺ dual‐overload and reactive oxygen species (ROS) attack toward 4T1 cells. Meanwhile, α‐CHCA and penthiopyrad disturbed the metabolic symbiotic environment by disrupting the TCA cycle and preventing lactate efflux to aggravate intracellular acidosis and promote Fenton‐like reaction of Cu⁺, enhancing the sensitivity of tumor cells to copper death and Ca²⁺ overload. Further, aided by the metabolism of symbiosis, the destroyed tumor cells further activate the polarization of M1 macrophages and the maturation and antigen cross‐presentation of dendritic cells (DCs), which further eliminate tumor cells. In summary, an amplified anti‐tumor dual‐ion interference strategy assisted by metabolic symbiotic destruction is established, which is of great significance in improving the clinical effect of ion therapy for tumors.