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

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.