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Metabolic modulation-driven self-reinforcing pyroptosis-STING nanoadjuvant for potentiated metalloimmunotherapy

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Bibliographic Details
Title: Metabolic modulation-driven self-reinforcing pyroptosis-STING nanoadjuvant for potentiated metalloimmunotherapy
Authors: Linzhu Zhang, Di Wang, Yiming Liu, Nailin Yang, Shumin Sun, Chunjie Wang, Duo Wang, Jihu Nie, Juan Qin, Lei Zhang, Liang Cheng, Haidong Zhu
Source: Bioactive Materials, Vol 53, Iss, Pp 641-655 (2025)
Publisher Information: Elsevier BV, 2025.
Publication Year: 2025
Subject Terms: cGAS-STING pathway, Glucose metabolism, CoF2 nanoenzymes, Transarterial embolization, QH301-705.5, Pyroptosis, TA401-492, Biology (General), Materials of engineering and construction. Mechanics of materials
Description: 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 GOCoF2, a self-amplifying pyroptosis-STING nanoadjuvant that integrates glucose oxidase (GOx) with cobalt fluoride (CoF2) nanoenzymes. This nanoadjuvant excelled in converting intratumoral H2O2 into reactive oxygen species (ROS), inducing cell pyroptosis. Its self-sustaining mechanism involved glucose depletion and continuous H2O2 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 Co2+ 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, GOCoF2 significantly inhibited primary and distant tumor progression via systemic immune activation. Additionally, we formulated GOCoF2-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.
Document Type: Article
Language: English
ISSN: 2452-199X
DOI: 10.1016/j.bioactmat.2025.07.040
Access URL: https://doaj.org/article/a412d08ed6f54595a147b7b7c6b3578d
Rights: CC BY NC ND
Accession Number: edsair.doi.dedup.....2336a98e805df6e1d1a77e46af33f5ab
Database: OpenAIRE
Description
Abstract: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 GOCoF2, a self-amplifying pyroptosis-STING nanoadjuvant that integrates glucose oxidase (GOx) with cobalt fluoride (CoF2) nanoenzymes. This nanoadjuvant excelled in converting intratumoral H2O2 into reactive oxygen species (ROS), inducing cell pyroptosis. Its self-sustaining mechanism involved glucose depletion and continuous H2O2 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 Co2+ 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, GOCoF2 significantly inhibited primary and distant tumor progression via systemic immune activation. Additionally, we formulated GOCoF2-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.
ISSN:2452199X
DOI:10.1016/j.bioactmat.2025.07.040