Multifunctional cascade nanosystem consumes glucose to trigger enhanced pyroptosis and cuproptosis for tumor immunotherapy
- 1Department of Ultrasound, China-Japan Union Hospital of Jilin University, Changchun, Jilin, 130033, China
- 2Institute of Translational Medicine, The First Hospital of Jilin University, Changchun, 130021, China
- 3State Key Laboratory of Inorganic Synthesis and Preparative Chemistry, College of Chemistry, Jilin University, Changchun, Jilin, 130012, China
Abstract
Immunogenic cell death (ICD) bridged local therapy and systemic immune activation by releasing damage-associated molecular patterns (DAMPs) that provoked antitumor responses. Pyroptosis, a pro-inflammatory cell death mode, induced local tumor demise and released cytokines that facilitated immune activation. In this study, we constructed a multifunctional cascade nanosystem CaO2/Cu-ZIF8/GOX (CaO2/CZ/GOX) that triggered mitochondrial oxidative stress through glucose consumption and ion homeostasis disturbance and cuproptosis, thereby amplifying tumor pyroptosis. The nanosystem utilized acid-responsive Cu-ZIF8 (CZ) as a carrier to load CaO2 and glucose oxidase (GOX). In the acidic tumor microenvironment (TME), CaO2 initiated cascaded H2O2 generation, while GOX concurrently consumed glucose and catalytically generated H2O2, synergistically exacerbating ion homeostasis disruption and mitochondrial oxidative stress. Meanwhile, Cu2+ released from Cu-ZIF8 participated in Fenton-like reactions to generate hydroxyl radicals (·OH), and accumulated Cu2+ further triggered FDX1-mediated cuproptosis. Collectively, these events resulted in reactive oxygen species (ROS) accumulation, ion homeostasis disruption, and mitochondrial damage, ultimately activating tumor cell pyroptosis and cuproptosis. In vitro and in vivo assays confirmed that CaO2/CZ/GOX NPs efficiently consumed glucose, selectively accumulated in tumor, and exhibited favorable biocompatibility. Moreover, they significantly inhibited Hepa1-6 tumor cell proliferation, effectively suppressed tumor recurrence and activated antitumor immunity. Overall, this nanosystem integrated a cascade of metabolic intervention, oxidative damage, cuproptosis, pyroptosis, and immune activation, offering a new strategy for tumor metabolic regulation and immune microenvironment remodeling.
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BibTeX
@article{dong2026multifunctional,
title = {{Multifunctional cascade nanosystem consumes glucose to trigger enhanced pyroptosis and cuproptosis for tumor immunotherapy}},
author = {Chunhui Dong and Lingyu Zhu and Heng Liu and Shuqiang Jin and Qimeihui Wang and Dengke Teng and Zhixia Sun and Bolun Liu and Hongyu Zhang and Peng Dong and Jiarui Du and Guoqing Sui and Hui Wang},
journal = {Materials Today Bio},
year = {2026},
month = oct,
doi = {10.1016/j.mtbio.2026.103772},
url = {https://doi.org/10.1016/j.mtbio.2026.103772},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - Multifunctional cascade nanosystem consumes glucose to trigger enhanced pyroptosis and cuproptosis for tumor immunotherapy
AU - Chunhui Dong
AU - Lingyu Zhu
AU - Heng Liu
AU - Shuqiang Jin
AU - Qimeihui Wang
AU - Dengke Teng
AU - Zhixia Sun
AU - Bolun Liu
AU - Hongyu Zhang
AU - Peng Dong
AU - Jiarui Du
AU - Guoqing Sui
AU - Hui Wang
PY - 2026
DA - 2026/10/26
JO - Materials Today Bio
DO - 10.1016/j.mtbio.2026.103772
UR - https://doi.org/10.1016/j.mtbio.2026.103772
AB - Immunogenic cell death (ICD) bridged local therapy and systemic immune activation by releasing damage-associated molecular patterns (DAMPs) that provoked antitumor responses. Pyroptosis, a pro-inflammatory cell death mode, induced local tumor demise and released cytokines that facilitated immune activation. In this study, we constructed a multifunctional cascade nanosystem CaO2/Cu-ZIF8/GOX (CaO2/CZ/GOX) that triggered mitochondrial oxidative stress through glucose consumption and ion homeostasis disturbance and cuproptosis, thereby amplifying tumor pyroptosis. The nanosystem utilized acid-responsive Cu-ZIF8 (CZ) as a carrier to load CaO2 and glucose oxidase (GOX). In the acidic tumor microenvironment (TME), CaO2 initiated cascaded H2O2 generation, while GOX concurrently consumed glucose and catalytically generated H2O2, synergistically exacerbating ion homeostasis disruption and mitochondrial oxidative stress. Meanwhile, Cu2+ released from Cu-ZIF8 participated in Fenton-like reactions to generate hydroxyl radicals (·OH), and accumulated Cu2+ further triggered FDX1-mediated cuproptosis. Collectively, these events resulted in reactive oxygen species (ROS) accumulation, ion homeostasis disruption, and mitochondrial damage, ultimately activating tumor cell pyroptosis and cuproptosis. In vitro and in vivo assays confirmed that CaO2/CZ/GOX NPs efficiently consumed glucose, selectively accumulated in tumor, and exhibited favorable biocompatibility. Moreover, they significantly inhibited Hepa1-6 tumor cell proliferation, effectively suppressed tumor recurrence and activated antitumor immunity. Overall, this nanosystem integrated a cascade of metabolic intervention, oxidative damage, cuproptosis, pyroptosis, and immune activation, offering a new strategy for tumor metabolic regulation and immune microenvironment remodeling.
SN - 2590-0064
ER -