Tumor Microenvironment Specific Regulation Ca‐Fe‐Nanospheres for Ferroptosis‐Promoted Domino Synergistic Therapy and Tumor Immune Response

Abstract Reactive oxygen species (ROS)‐mediated emerging treatments exhibit unique advantages in cancer therapy in recent years. While the efficacy of ROS‐involved tumor therapy is greatly restricted by complex tumor microenvironment (TME). Herein, a dual‐metal CaO 2 @CDs‐Fe (CCF) nanosphere, with TME response and regulation capabilities, are proposed to improve ROS lethal power by a multiple cascade synergistic therapeutic strategy with domino effect. In response to weak acidic TME, CCF will decompose, accompanied with intracellular Ca 2+ upregulated and abundant H 2 O 2 and O 2 produced to reverse antitherapeutic TME. Then the exposed CF cores can act as both Fenton agent and sonosensitizer to generate excessive ROS in the regulated TME for enhanced synergistic CDT/SDT. In combination with calcium overloading, the augmented ROS induced oxidative stress will cause more severe mitochondrial damage and cellular apoptosis. Furthermore, CCF can also reduce GPX4 expression and enlarge the lipid peroxidation, causing ferroptosis and apoptosis in parallel. These signals of damage will finally initiate damage‐associated molecular patterns to activate immune response and to realize excellent antitumor effect. This outstanding domino ROS/calcium loading synergistic effect endows CCF with excellent anticancer effect to efficiently eliminate tumor by apoptosis/ferroptosis/ICD both in vitro and in vivo.