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  3. Disrupting intracellular redox homeostasis through copper-driven dual cell death to induce anti-tumor immunotherapy

Disrupting intracellular redox homeostasis through copper-driven dual cell death to induce anti-tumor immunotherapy

  • Biomaterials. 2025 Jun 23:324:123523. doi: 10.1016/j.biomaterials.2025.123523.
Zhenxin Wang 1,  Yuting Li 2,  Congcong Wang 3,  Jun Lan 4,  Jiale Li 2,  Guanhong Liu 5,  Yuxing Chen 6,  Dehong Yu 7,  Zhao Liu 8,  Fenglei Gao 9
Affiliations

Affiliations

  • 1 Department of Thyroid and Breast Surgery, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, 221002, China; Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, Jiangsu, 221004, China; Department of Orthopaedic Surgery, The First Affiliated Hospital of Chongqing Medical University, Yuzhong, Chongqing, 400016, China.
  • 2 Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, Jiangsu, 221004, China.
  • 3 Department of Orthopedics, The Affiliated Huai'an Hospital of Xuzhou Medical University, The Second People's Hospital of Huai'an, Huai'an, 223002, China.
  • 4 Department of Orthopaedic Surgery, Lishui Central Hospital and Fifth Affiliated Hospital of Wenzhou Medical University, Lishui 323000, Zhejiang Province, China.
  • 5 Department of Thyroid and Breast Surgery, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, 221002, China; Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, Jiangsu, 221004, China.
  • 6 Department of Orthopaedic Surgery, The First Affiliated Hospital of Chongqing Medical University, Yuzhong, Chongqing, 400016, China.
  • 7 The Affiliated Pizhou Hospital of Xuzhou Medical University, Jiangsu, 221399, China. Electronic address: 15380117222@163.com.
  • 8 Department of Thyroid and Breast Surgery, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, 221002, China; Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, Jiangsu, 221004, China. Electronic address: xylzhao9999@163.com.
  • 9 Department of Thyroid and Breast Surgery, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, 221002, China; Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, Jiangsu, 221004, China; The Affiliated Pizhou Hospital of Xuzhou Medical University, Jiangsu, 221399, China. Electronic address: jsxzgfl@sina.com.
PMID: 40592037 DOI: 10.1016/j.biomaterials.2025.123523
Abstract

The abnormality of redox homeostasis within tumors serves as a fundamental driving force for their growth and metastasis. Based on the coordination chemistry of specific metal ions, the precise modulation of intracellular reduction mechanisms by blocking key enzyme activities is expected to become an emerging anti-tumor strategy. Here, we developed a copper-based nanoinducer (CST NPs) that simultaneously induces both Cuproptosis and Disulfidptosis by disrupting intracellular copper ion homeostasis. In the acidic tumor microenvironment (TME), CST NPs can inhibit glucose-6-phosphate dehydrogenase (G6PD) activity, thereby reducing NADPH production, decreasing cysteine conversion, and significantly depleting the substrate required for glutathione (GSH) synthesis. Subsequently, a substantial amount of Reactive Oxygen Species (ROS) can be generated through the cascade catalysis of copper ions contained in CST NPs. Concurrently, the cellular redox homeostasis is further disrupted with the widespread depletion of GSH by Cu2+. In addition, CST NPs have been demonstrated to directly induce cytoskeletal contraction and rupture, resulting in membrane disruption and the subsequent exposure and release of tumor-associated antigens (TAAs) and damage-associated molecular patterns (DAMPs). This process initiates a potent immune response by reprogramming the immunosuppressive TME. This work presents a novel paradigm that precisely regulates intracellular copper ion homeostasis to induce both Cuproptosis and Disulfidptosis, offering a new theoretical basis for further elucidating the potential mechanisms of copper-induced cell death.

Keywords

Copper; Cuproptosis; Disulfidptosis; Immunotherapy; NADPH.

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