Copper‐Doped Polydopamine Nanoparticles‐Mediated GSH/GPX4‐Depleted Ferroptosis and Cuproptosis Sensitizes Lung Tumor to Checkpoint Blockade Immunotherapy

Abstract Immune checkpoint blockade (ICB) therapy offers hope for improved outcomes in lung cancer treatment, but its effectiveness is restricted by the presence of an immunosuppressive tumor microenvironment (TME), resulting in a limited response rate (< 20%). Here this study reports a tumor‐site glutathione (GSH)/glutathione peroxidase (GPX4) dual‐depletion strategy to induce tumor ferroptosis and amplify cuproptosis via a GSH‐responsive polydopamine‐based hybrid nanoparticle (termed CACuPDA). This approach triggers cellular lysis to reverse immunosuppressive TME and further enhance the therapeutic efficacy of lung tumors combined with anti‐PD‐L1‐based ICB therapy. The released cinnamaldehyde (CA) can stimulate reactive oxygen species production, while Cu 2+ can directly deplete GSH and suppress GPX4. Interestingly, Cu 2+ induces cuproptosis by downregulating ferredoxin (FDX1) expression, whereas reduced Cu + can catalyze hydroxyl radicals (·OH) generation from overexpressed H 2 O 2 at the tumor site. The redox imbalance amplifies ferroptosis and cuproptosis in lung tumor cells, releasing substantial amounts of cellular contents into the immunosuppressive TME, as evidenced by an increased amount of cytotoxic T cells and a decreased amount of immunosuppressive Treg cells. In addition, in vivo experimental results revealed that CACuPDA enhanced the therapeutic effect of anti‐PD‐L1 by about fivefold for lung tumor treatment, providing a promising strategy to improve ICB therapy for lung tumors.