Mesoporous dual-atom nanozyme induced cuproptosis and apoptosis for boosting immunogenic cell death along with reprogramming tumor immune-suppressive microenvironment

Immune checkpoint inhibitors (ICIs) are among the most prominent immunotherapies for cancer and have been approved as first-line treatments for various tumors. Although some patients experience long-lasting responses, the objective response rate (ORR) of ICIs as monotherapy is relatively low due to the complexity of the tumor microenvironment and the heterogeneity of tumors. Maximizing the benefits of this novel therapeutic approach for a greater number of patients remains a research focus in the field of anticancer treatment. Here, we have investigated a novel Pt/Cu Dual-Atom Nanozyme (Pt/Cu DAzyme) which is engineered by the successive growth of metal-nanocrystals on the assembled surfactant templates. This DAzyme can significantly enhance the intracellular copper ion levels in tumor cells, inducing cuproptosis. Additionally, the Pt/Cu DAzyme exhibits excellent dual enzyme catalytic activity as both glutathione oxidase (GSHOx) and peroxidase (POD) activity, which not only reduces glutathione (GSH) levels in tumors to enhance cuproptosis but also converts intracellular H 2 O 2 into •OH to kill tumor cells. Furthermore, the Pt/Cu DAzyme demonstrates a strong photothermal effect, with its enzymatic reactions being enhanced at mildly elevated temperatures. This DAzyme effectively kills tumors and activates the body’s robust immune system, reshaping the tumor immune-suppressive microenvironment and significantly increasing the therapeutic response rate to αPD-L1. It not only achieves complete ablation of primary tumors but also markedly inhibits the progression of distal tumors and distant metastasis. This study aims to develop new combination therapy strategies to enhance the efficacy of ICIs and promote their advancement in the field of cancer immunotherapy.