their quality of life. [1] Despite local therapy, approximately one-third of patients will relapse and develop metastatic diseases. [2] In recent years, immunotherapy has made great progress. Anti-programmed cell death protein ligand-1 antibody (αPD-L1) has been approved by the US Food and Drug Administration for bladder cancer treatment since 2016, the usage of which spanning from non-muscle-invasive to metastatic disease. [3] However, many bladder cancer patients fail to respond to these treatments. [4] On the one hand, many tumors are immune "cold tumors" with an immunosuppressive tumor microenvironment (TME) that do not respond to existing immunotherapeutic agents. [5] On the other hand, αPD-L1 is a viable choice only for programmed cell death proteinligand 1 (PD-L1) positive bladder cancer patients, while PD-L1 expression varies between individuals. [6] Recent studies indicated that intra-tumoral copper (Cu) levels in tumors could affect PD-L1 expression, but enhancing the effect of αPD-L1 by regulating Cu levels has not been reported in vivo studies so far. [7] Cu is an extremely important intracellular trace element that plays a key role in maintaining redox Cuproptosis is a new cell death that depends on copper (Cu) ionophores to transport Cu into cancer cells, which induces cell death. However, existingCu 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.

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A simple and efficient synthesis of tribenzohexadehydro[12]annulene and related derivatives in the ionic liquid 1-butyl-3-methylimidazolium tetrafluoroborate is described. A Sonogashira coupling reaction is the key step. In this system, the amount of CuI normally used can be reduced so that homocoupling is minimized.