Bai Binglong, Zheng Zihao, Zhu Bingzi, Wu Jianlin, Xu Yizhou, Zhong Xihao, Deng Wenhai, Wang Xiang, Zhao Shengsheng, You Tao, Huang Yingpeng, Sun Weijian, Shen Xian, Lu Xufeng
Department of Gastrointestinal Surgery, Zhejiang International Scientific and Technological Cooperation Base of Translational Cancer Research, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China.
Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China.
Mater Today Bio. 2025 Jul 26;34:102135. doi: 10.1016/j.mtbio.2025.102135. eCollection 2025 Oct.
Chemoresistance remains a tremendous challenge in the clinical treatment of hepatocellular carcinoma (HCC). However, the induction of ferroptosis, a form of regulated cell death, could overcome chemoresistance and improve treatment outcomes for HCC patients. In this study, we constructed a covalent organic framework (COF)-based nanoplatform (SRF@Fe(III)-COF) that combines ferroptosis induction and chemotherapy for dual-mode HCC treatment. The peroxidase- and glutathione oxidase-like activities of the nanoplatform are mediated by ferric (Fe(III)) ions, which act as excellent ferroptosis executors, and the encapsulated sorafenib (SRF) can attenuate tumor cell resistance to ferroptosis, effectively facilitating chemo-ferroptosis. Furthermore, SRF@Fe(III)-COF was found to trigger immunogenic cell death and stimulate a pronounced immune response by inducing robust ferroptosis. SRF@Fe(III)-COF synergized with programmed death receptor-1 (PD-1) immune checkpoint blockade to effectively restrict the growth of primary and distal H22 tumors by recruiting tumor-infiltrating lymphocytes and establishing systemic immune memory. Overall, our study revealed that the combination of a chemotherapeutic agent with a ferroptosis inducer is a promising approach for improving HCC immunotherapy.
化疗耐药仍然是肝细胞癌（HCC）临床治疗中的巨大挑战。然而，诱导铁死亡（一种程序性细胞死亡形式）可以克服化疗耐药并改善HCC患者的治疗效果。在本研究中，我们构建了一种基于共价有机框架（COF）的纳米平台（SRF@Fe(III)-COF），其将铁死亡诱导与化疗相结合用于双模式HCC治疗。纳米平台的过氧化物酶样和谷胱甘肽氧化酶样活性由铁离子（Fe(III)）介导，铁离子是优异的铁死亡执行者，且包封的索拉非尼（SRF）可减弱肿瘤细胞对铁死亡的抗性，有效促进化学铁死亡。此外，发现SRF@Fe(III)-COF通过诱导强烈的铁死亡触发免疫原性细胞死亡并刺激显著的免疫反应。SRF@Fe(III)-COF与程序性死亡受体-1（PD-1）免疫检查点阻断协同作用，通过募集肿瘤浸润淋巴细胞并建立全身免疫记忆有效限制原发性和远处H22肿瘤的生长。总体而言，我们的研究表明化疗药物与铁死亡诱导剂联合使用是改善HCC免疫治疗的一种有前景的方法。
