Targeted Intracellular Copper Reservoir Enhances Liver Cancer Immunotherapy

  • Small. 2025 Sep;21(36):e02783. doi: 10.1002/smll.202502783.
Tianao Xie  1  2  3 ,  Yukai Shan  1  2  3 ,  Win Topatana  1  2  3 ,  Taorui Yang  4 ,  Ruijing Shen  1  2  3 ,  Shijie Li  1  2  3 ,  Jiadong Chen  5 ,  Yiyuan Zhu  6 ,  Ziyi Lu  1  2  3 ,  Yeling Liu  7 ,  Tianen Chen  1  2  3 ,  Yujie Gao  8 ,  Yuchao Sun  1  2  3 ,  Xiujun Cai  1  2  3 ,  Sarun Juengpanich  1  2  3 ,  Mingyu Chen  1  2  3  9
Affiliations
  • 1. Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University, Hangzhou, 310016, P. R. China.
  • 2. National Engineering Research Center of Innovation and Application of Minimally Invasive Instruments, Sir Run-Run Shaw Hospital, Zhejiang University, Hangzhou, 310016, P. R. China.
  • 3. School of Medicine, Zhejiang University, Hangzhou, 310058, P. R. China.
  • 4. College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, P. R. China.
  • 5. Department of Chemistry, Zhejiang University, Hangzhou, 310016, P. R. China.
  • 6. School of Materials Science and Engineering, Zhejiang University, Hangzhou, 310058, P. R. China.
  • 7. Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Beijing, 100730, P. R. China.
  • 8. Rizhao Emergency Management Support Center, Rizhao, 276800, P. R. China.
  • 9. State Key Laboratory of Advanced Drug Delivery and Release Systems, Shandong Luye Pharmaceutical Co., Ltd., Yantai, Shandong, 264003, P. R. China.
PMID: 40685755 DOI: 10.1002/smll.202502783
Abstract

Hepatocellular carcinoma (HCC) is commonly classified as a "cold tumor" due to its low immunogenicity and poor response to conventional immunotherapies. Reprogramming the tumor immune microenvironment (TIME) via Cuproptosis presents a promising strategy to enhance immunotherapies. Herein, sono-activatable N,N,N',N'-tetrakis(2-pyridinylmethyl)-1,2-ethanediamine (TPEN)-encapsulated cancer-targeted nanoparticles (STCNs) designed to modulate the TIME and potentiate immunotherapy through endogenous Cuproptosis are reported, termed "endogenous Cuproptosis immunopromotion". STCNs are rapidly internalized by HCC via folate-mediated endocytosis, and ultrasound irradiation triggers the release of TPEN. TPEN then chelates Cu2⁺ from superoxide dismutase, initiating a Fenton-like reaction induced by glutathione that produces Reactive Oxygen Species (ROS) and Cu⁺. This cascade induces Cuproptosis and immunogenic cell death (ICD), promoting robust cytotoxic T lymphocyte infiltration in HCC. The combination of STCNs with anti-programmed cell death protein 1 (PD1) therapy demonstrates significant anti-tumor efficacy in vivo. Moreover, this strategy exhibits similar effectiveness in Other solid tumor models, underscoring its broad therapeutic potential. These findings provide a promising framework for enhancing immunotherapy in cold tumors, paving the way for future Cancer treatments.

Keywords
cuproptosis; hepatocellular carcinoma; immunogenic cell death; metal‐organic frameworks; sonodynamic therapy.
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