Zhang Linzhu, Wang Di, Liu Yiming, Yang Nailin, Sun Shumin, Wang Chunjie, Wang Duo, Nie Jihu, Qin Juan, Zhang Lei, Cheng Liang, Zhu Haidong
Center of Interventional Radiology & Vascular Surgery, Department of Radiology, Nurturing Center of Jiangsu Province for State Laboratory of AI Imaging & Interventional Radiology (Southeast University), Basic Medicine Research and Innovation Center of Ministry of Education, Zhongda Hospital, Medical School, Southeast University, 87 Dingjiaqiao Road, Nanjing, 210009, China.
Institute of Functional Nano & Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials & Devices, Soochow University, Suzhou, 215123, China.
Bioact Mater. 2025 Jul 30;53:641-655. doi: 10.1016/j.bioactmat.2025.07.040. eCollection 2025 Nov.
Pyroptosis is a critical process that triggers inflammatory responses and mitochondrial DNA (mtDNA) release, thereby activating the cGAS-STING pathway. However, tumor metabolism, particularly glycolysis, often suppresses immune activation. To address this, we developed GOCoF, a self-amplifying pyroptosis-STING nanoadjuvant that integrates glucose oxidase (GOx) with cobalt fluoride (CoF) nanoenzymes. This nanoadjuvant excelled in converting intratumoral HO into reactive oxygen species (ROS), inducing cell pyroptosis. Its self-sustaining mechanism involved glucose depletion and continuous HO generation, ensuring persistent catalytic activity. This metabolic manipulation and induction of oxidative stress significantly enhance pyroptosis in tumor cells. The released mtDNA subsequently activated the cGAS-STING pathway, with Co further amplifying this effect. Notably, glucose-dependent TREX2 inhibition intensified cGAS-STING activation through metabolic regulation, leading to a strong immune response and tumor growth suppression. When combined with immune checkpoint blockade therapy, GOCoF significantly inhibited primary and distant tumor progression via systemic immune activation. Additionally, we formulated GOCoF-lipiodol for transarterial embolization, which demonstrated superior efficacy in a rat model of orthotopic hepatocellular carcinoma. This study not only sheds light on the intricate relationship between tumor metabolism and immune regulation but also introduces a novel therapeutic approach for hepatocellular carcinoma.
细胞焦亡是一个触发炎症反应和线粒体DNA（mtDNA）释放的关键过程，从而激活cGAS-STING通路。然而，肿瘤代谢，尤其是糖酵解，常常抑制免疫激活。为了解决这个问题，我们开发了GOCoF，一种将葡萄糖氧化酶（GOx）与氟化钴（CoF）纳米酶整合的自扩增细胞焦亡-STING纳米佐剂。这种纳米佐剂在将肿瘤内的H2O2转化为活性氧（ROS）、诱导细胞焦亡方面表现出色。其自我维持机制涉及葡萄糖消耗和持续的H2O2生成，确保了持续的催化活性。这种代谢操纵和氧化应激诱导显著增强了肿瘤细胞中的细胞焦亡。释放的mtDNA随后激活了cGAS-STING通路，Co进一步放大了这种效应。值得注意的是，葡萄糖依赖性TREX2抑制通过代谢调节增强了cGAS-STING激活，导致强烈的免疫反应和肿瘤生长抑制。当与免疫检查点阻断疗法联合使用时，GOCoF通过全身免疫激活显著抑制原发性和远处肿瘤进展。此外，我们制备了用于经动脉栓塞的GOCoF-碘油，其在原位肝细胞癌大鼠模型中显示出卓越的疗效。这项研究不仅揭示了肿瘤代谢与免疫调节之间的复杂关系，还为肝细胞癌引入了一种新的治疗方法。
