Disulfidptosis and Enzymatic‐Therapy Augmented Cuproptosis via Adding Spear and Discarding Shield Strategy

Abstract Cuproptosis, a new copper‐dependent cell death modality, is increasingly acknowledged for its crucial role in anticancer therapy. It is still hampered by weak activation and the overexpression of cellular self‐protective components, such as glutathione (GSH) and copper efflux transporter ATPase. Here, the Cu ₂ O‐based nanoactivators (CGH NAs) are prepared to enhance the “offensive” of cuproptosis toward tumor cells by “adding spears (Cu ⁺ )” and “discarding shields (GSH, ATPase)” simultaneously. Initially, the glucose oxidase (GOx)‐mediated gluconic acid production can promote the release of Cu⁺ from Cu ₂ O for effective cuproptosis activation. Meanwhile, disulfidptosis, a recently found programmed cell death, can be induced by CGH NAs, which inhibit the cystine‐to‐cysteine metabolic pathway and thereby block copper chelator GSH biosynthesis. Next, Cu ₂ O‐induced self‐cascade enzymatic reactions (OXD, SOD, and POD) are first achieved, which lead to significant mitochondrial dysfunction. Benefiting from the dual inhibition of mitochondrial metabolism and GOx‐induced glycolysis, the provision of ATP is fundamentally blocked, thereby further downregulating the ATPase to prevent the efflux of copper ions. Collectively, the “adding spear and discarding shield” strategy dramatically inhibits primary tumor growth in vivo (73.5%). This work first demonstrates disulfidptosis‐augmented cuproptosis, and will also provide unique inspiration for regulating both the positive and negative directions in cuproptosis.