Xie Tianao, Shan Yukai, Topatana Win, Yang Taorui, Shen Ruijing, Li Shijie, Chen Jiadong, Zhu Yiyuan, Lu Ziyi, Liu Yeling, Chen Tianen, Gao Yujie, Sun Yuchao, Cai Xiujun, Juengpanich Sarun, Chen Mingyu
Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University, Hangzhou, 310016, P. R. China.
National Engineering Research Center of Innovation and Application of Minimally Invasive Instruments, Sir Run-Run Shaw Hospital, Zhejiang University, Hangzhou, 310016, P. R. China.
Small. 2025 Sep;21(36):e02783. doi: 10.1002/smll.202502783. Epub 2025 Jul 20.
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⁺ 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.
肝细胞癌（HCC）通常因其免疫原性低且对传统免疫疗法反应不佳而被归类为“冷肿瘤”。通过铜死亡对肿瘤免疫微环境（TIME）进行重编程是一种增强免疫疗法的有前景的策略。在此，报道了一种可声激活的、封装了N,N,N',N'-四(2-吡啶甲基)-1,2-乙二胺（TPEN）的癌症靶向纳米颗粒（STCNs），其旨在通过内源性铜死亡来调节TIME并增强免疫疗法，称为“内源性铜死亡免疫促进”。STCNs通过叶酸介导的内吞作用被HCC快速内化，超声照射触发TPEN的释放。然后，TPEN从超氧化物歧化酶螯合Cu⁺，引发由谷胱甘肽诱导的类Fenton反应，产生活性氧（ROS）和Cu⁺。这一级联反应诱导铜死亡和免疫原性细胞死亡（ICD），促进细胞毒性T淋巴细胞在HCC中的大量浸润。STCNs与抗程序性细胞死亡蛋白1（PD1）疗法联合在体内显示出显著的抗肿瘤疗效。此外，该策略在其他实体瘤模型中也表现出相似的有效性，凸显了其广泛的治疗潜力。这些发现为增强冷肿瘤中的免疫疗法提供了一个有前景的框架，为未来的癌症治疗铺平了道路。
