Cuproptosis Induced by ROS Responsive Nanoparticles with Elesclomol and Copper Combined with αPD‐L1 for Enhanced Cancer Immunotherapy

Abstract Cuproptosis is a new cell death that depends on copper (Cu) ionophores to transport Cu into cancer cells, which induces cell death. However, existing Cu ionophores are small molecules with a short blood half‐life making it hard to transport enough Cu into cancer cells. Herein, a reactive oxygen species (ROS)‐sensitive polymer (PHPM) is designed, which is used to co‐encapsulate elesclomol (ES) and Cu to form nanoparticles (NP@ESCu). After entering cancer cells, ES and Cu, triggered by excessive intracellular ROS, are readily released. ES and Cu work in a concerted way to not only kill cancer cells by cuproptosis, but also induce immune responses. In vitro, the ability of NP@ESCu to efficiently transport Cu and induce cuproptosis is investigated. In addition, the change in the transcriptomes of cancer cells treated with NP@ESCu is explored by RNA‐Seq. In vivo, NP@ESCu is found to induce cuproptosis in the mice model with subcutaneous bladder cancer, reprograming the tumor microenvironment. Additionally, NP@ESCu is further combined with anti‐programmed cell death protein ligand‐1 antibody (αPD‐L1). This study provides the first report of combining nanomedicine that can induce cuproptosis with αPD‐L1 for enhanced cancer therapy, thereby providing a novel strategy for future cancer therapy.