Bimetallic Peroxide Nanocomposites‐Driven Redox Dyshomeostasis to Activate Sequential Cuproptosis and Pyroptosis for Amplified Tumor Immunotherapy

Hyaluronic acid‐modified bimetallic peroxide nanocomposites (MgO2‐CuO2@HA) are designed for synergistic tumor therapy. The nanocomposites release Mg2+, H2O2, and Cu2+ in tumor cells, induce cuproptosis via Cu+‐mediated protein aggregation, and activate pyroptosis through caspase‐1/gasdermin D pathways for inducing immunogenic cell death, collectively promote the activation of CD8+ T cells by released Mg2+ for cancer immunotherapy with minimal systemic toxicity. Abstract Although metal peroxides are extensively employed in tumor therapy, novel synergistic tumor treatment approaches based on the combination of multiple types of metal peroxides are still lacking and warrant further exploration. To overcome this challenge, hyaluronic acid (HA)‐modified bimetallic peroxide nanocomposites (MgO2‐CuO2@HA NCs) are developed by combining magnesium peroxide (MgO2) nanosheets and short‐grained copper peroxide (CuO2) nanodots. By modifying HA to enhance tumor targeting and stability, MgO2‐CuO2@HA NCs leverage pH‐dependent decomposition to release Mg2+, H2O2, and Cu2+ under acidic conditions, thereby initiating Fenton‐like reactions for the generation of hydroxyl radicals (•OH), while simultaneously depleting glutathione to generate Cu+. This process induces cuproptosis through the Cu+‐mediated oligoaggregation of dihydrolipoamide S‐acetyltransferase. Additionally, enhanced •OH activates pyroptosis via the caspase‐1/gasdermin D pathway. Cuproptosis and pyroptosis can induce immunogenic cell death, thereby triggering the anti‐tumor immune responses. Notably, released Mg2+ can enhance the activation of CD8+ T cells by promoting the conformational activation of leukocyte function‐associated antigen 1. Therefore, this study establishes a novel paradigm for synergistic anti‐tumor immunotherapy based on bimetallic peroxide nanocomposites, offering promising prospects for clinical immunotherapy. Hyaluronic acid-modified bimetallic peroxide nanocomposites (MgO 2 -CuO 2 @HA) are designed for synergistic tumor therapy. The nanocomposites release Mg 2+, H 2 O 2, and Cu 2+ in tumor cells, induce cuproptosis via Cu + -mediated protein aggregation, and activate pyroptosis through caspase-1/gasdermin D pathways for inducing immunogenic cell death, collectively promote the activation of CD8 + T cells by released Mg 2+ for cancer immunotherapy with minimal systemic toxicity. Abstract Although metal peroxides are extensively employed in tumor therapy, novel synergistic tumor treatment approaches based on the combination of multiple types of metal peroxides are still lacking and warrant further exploration. To overcome this challenge, hyaluronic acid (HA)-modified bimetallic peroxide nanocomposites (MgO 2 -CuO 2 @HA NCs) are developed by combining magnesium peroxide (MgO 2 ) nanosheets and short-grained copper peroxide (CuO 2 ) nanodots. By modifying HA to enhance tumor targeting and stability, MgO 2 -CuO 2 @HA NCs leverage pH-dependent decomposition to release Mg 2+, H 2 O 2, and Cu 2+ under acidic conditions, thereby initiating Fenton-like reactions for the generation of hydroxyl radicals (•OH), while simultaneously depleting glutathione to generate Cu +. This process induces cuproptosis through the Cu + -mediated oligoaggregation of dihydrolipoamide S-acetyltransferase. Additionally, enhanced •OH activates pyroptosis via the caspase-1/gasdermin D pathway. Cuproptosis and pyroptosis can induce immunogenic cell death, thereby triggering the anti-tumor immune responses. Notably, released Mg 2+ can enhance the activation of CD8 + T cells by promoting the conformational activation of leukocyte function-associated antigen 1. Therefore, this study establishes a novel paradigm for synergistic anti-tumor immunotherapy based on bimetallic peroxide nanocomposites, offering promising prospects for clinical immunotherapy. Advanced Science, EarlyView.