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A Self-Priming Pyroptosis-Inducing Agent for Activating Anticancer Immunity
Yanjie Li1,2,3,4,5,6, Hanxin Feng1,2,3,4,5,6, Huang Yang1,7
1Department of Hepatobiliary and Pancreatic Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, China.
Abstract:
Pyroptosis, a form of programmed cell death mediated by the gasdermin family, has emerged as a promising strategy for inducing anti-tumor immunity. However, efficiently inducing pyroptosis in tumor cells remains a significant challenge due to the limited activation of key mediators like caspases in tumor tissues. Herein, a self-priming pyroptosis-inducing agent (MnNZ@OMV) is developed by integrating outer membrane vesicles (OMVs) with manganese dioxide nanozymes (MnNZ) to trigger pyroptosis in tumor cells. OMVs, derived from Escherichia coli, are coated onto spiny MnNZ to prepare MnNZ@OMV. Once internalized by tumor cells, MnNZ@OMV responds to elevated intracellular glutathione (GSH) levels, releasing Mn2⁺ and OMV components. This leads to GSH depletion and Mn2⁺-catalyzed reactive oxygen species generation, which triggers NF-κB translocation and prime caspase-11 expression. Subsequently, lipopolysaccharides from OMVs activate caspase-11, resulting in GSDMD cleavage and pyroptosis induction. MnNZ@OMV significantly induces tumor pyroptosis in vivo, promoting dendritic cell maturation and CD8⁺ T cell activation, leading to robust anti-tumor effects. Collectively, this study presents a novel self-priming approach for inducing tumor cell pyroptosis through the noncanonical caspase-11/GSDMD pathway, offering a promising avenue for future cancer immunotherapy.
Insights
This study introduces MnNZ@OMV, a novel agent that effectively triggers pyroptosis in tumor cells. This approach enhances anti-tumor immunity by activating immune cells and promoting cancer immunotherapy.
Area of Science:
- Biotechnology
- Immunology
- Materials Science
Background:
- Pyroptosis, a programmed cell death pathway, is a promising strategy for anti-tumor immunity.
- Challenges exist in efficiently inducing pyroptosis in tumor cells due to limited caspase activation.
Purpose of the Study:
- To develop a self-priming pyroptosis-inducing agent (MnNZ@OMV) for enhanced anti-tumor immunity.
- To investigate the mechanism of MnNZ@OMV-induced pyroptosis via the noncanonical caspase-11/GSDMD pathway.
Main Methods:
- Integration of outer membrane vesicles (OMVs) with manganese dioxide nanozymes (MnNZ) to create MnNZ@OMV.
- In vitro and in vivo studies to assess MnNZ@OMV's ability to induce pyroptosis, deplete glutathione, generate reactive oxygen species, and activate immune cells.
Main Results:
- MnNZ@OMV effectively induces pyroptosis in tumor cells by responding to intracellular glutathione (GSH).
- The agent triggers NF-κB translocation, primes caspase-11 expression, and leads to GSDMD cleavage.
- In vivo studies demonstrated MnNZ@OMV's ability to promote dendritic cell maturation and CD8+ T cell activation, resulting in significant anti-tumor effects.
Conclusions:
- A novel self-priming pyroptosis-inducing agent (MnNZ@OMV) was successfully developed.
- This approach utilizes the noncanonical caspase-11/GSDMD pathway for tumor cell pyroptosis induction.
- MnNZ@OMV shows significant potential as a therapeutic strategy for cancer immunotherapy.
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