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

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) was designed, which was 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, were readily released. ES and Cu worked 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 was investigated. In addition, the change in the transcriptomes of cancer cells treated with NP@ESCu was explored by RNA-Seq. In vivo, NP@ESCu was found to induce cuproptosis in the mice model with subcutaneous bladder cancer, reprograming the tumor microenvironment. Additionally, NP@ESCu was 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. This article is protected by copyright. All rights reserved.