NADPH Oxidases-Inspired Reactive Oxygen Biocatalysts with Electron-Rich Pt Sites to Potently Amplify Immune Checkpoint Blockade Therapy

Abstract

Clinical immune checkpoint blockade (ICB)-based immunotherapy of malignant tumors only elicits durable responses in a minority of patients, primarily due to the highly immunosuppressive tumor microenvironment. Although inducing immunogenic cell death (ICD) through reactive oxygen biocatalyst represents an attractive therapeutic strategy to amplify ICB, currently reported biocatalysts encounter insurmountable challenges in achieving high ROS-generating activity to induce potent ICD. Here, inspired by the natural catalytic characteristics of NADPH oxidases, the design of efficient, robust, and electron-rich Pt-based redox centers on the non-stoichiometric W₁₈O₄₉ substrates (Pt─WO_x) to serve as bioinspired reactive oxygen biocatalysts to potently activate the ICD, which eventually enhance cancer immune responses and amplifies the ICB-based immunotherapy is reported. These studies demonstrate that the Pt─WO_x exhibits rapid electron transfer capability and can promote the formation of electron-rich and low oxophilic Pt redox centers for superior reactive oxygen biocatalysis, which enables the Pt─WO_x-based inducers to trigger endoplasmic reticulum stress directly and stimulate immune responses potently for amplifying the anti-PD-L1-based ICB therapy. This bioinspired design provides a straightforward strategy to engineer efficient, robust, and electron-rich reactive oxygen biocatalysts and also opens up a new avenue to create efficient ICD inducers for primary/metastatic tumor treatments.