Targeted Intracellular Copper Reservoir Enhances Liver Cancer Immunotherapy

作者：Tian‐Ao Xie, Yukai Shan, Win Topatana, Taorui Yang, Ruijing Shen, Shijie Li, Jiadong Chen, Yiyuan Zhu, Ziyi Lu, Yeling Liu, Tianen Chen, Yujie Gao, Yuchao Sun, Xiujun Cai, Sarun Juengpanich, Mingyu Chen · 发表于：Small · 年份：2025 · DOI：10.1002/smll.202502783 · 被引用次数：9 · 研究领域：Advanced Nanomaterials in Catalysis、Nanoplatforms for cancer theranostics、Nanocluster Synthesis and Applications

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 Cu 2 ⁺ 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.