Chitosan activates NLRP3 inflammasome and cGAS-STING to suppress cancer progression through hexokinase 2 dissociation and mitochondrial dysfunction.

IF 13.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL
Theranostics Pub Date : 2025-07-25 eCollection Date: 2025-01-01 DOI:10.7150/thno.112009
Lu Li, Liting You, Zhenfei Bi, Ziqi Zhang, Binwu Ying, Min Luo, Xiawei Wei
{"title":"Chitosan activates NLRP3 inflammasome and cGAS-STING to suppress cancer progression through hexokinase 2 dissociation and mitochondrial dysfunction.","authors":"Lu Li, Liting You, Zhenfei Bi, Ziqi Zhang, Binwu Ying, Min Luo, Xiawei Wei","doi":"10.7150/thno.112009","DOIUrl":null,"url":null,"abstract":"<p><p><b>Background:</b> Chitosan, a natural polysaccharide with known immunostimulatory potential, has shown promise in cancer therapy. However, its direct role in modulating antitumor immunity and the underlying mechanisms remain unclear. This study aimed to explore how unmodified chitosan influences tumor progression and immune responses through innate immune signaling pathways. <b>Methods:</b> Murine tumor models (CT26, B16-F10) were used to evaluate the antitumor effects of chitosan in vivo. Flow cytometry and histological analyses assessed changes in immune cell infiltration. Primary macrophages and gene knockout models were used to investigate the molecular mechanisms, including inflammasome activation, mitochondrial function, and hexokinase 2 (HK2) location, via ELISA, western blotting, mitochondrial assays. <b>Results:</b> Chitosan treatment suppressed tumor growth and metastasis, while promoting infiltration of neutrophils, monocytes, and activated T cells in the tumor microenvironment. Mechanistically, chitosan and its bioactive degradation product, N-acetylglucosamine (NAG), induced the dissociation of HK2 from mitochondria, triggering mitochondrial dysfunction, ROS overproduction, and mtDNA release. These signals jointly activated both the NLRP3 inflammasome and the cGAS-STING pathway. The antitumor effect of chitosan was attenuated in <i>Nlrp3</i> <sup>-/-</sup> and <i>Sting</i> <sup>-/-</sup> mice, confirming the essential roles of both pathways. <b>Conclusions:</b> Chitosan orchestrates dual activation of NLRP3 and cGAS-STING signaling via HK2 dissociation and mitochondrial dysfunction, reprogramming the tumor immune microenvironment and enhancing antitumor immunity. These findings support chitosan's potential as a multifunctional immunoadjuvant for improving immunotherapy in resistant cancers.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 16","pages":"8473-8487"},"PeriodicalIF":13.3000,"publicationDate":"2025-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12374619/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Theranostics","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.7150/thno.112009","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/1/1 0:00:00","PubModel":"eCollection","JCR":"Q1","JCRName":"MEDICINE, RESEARCH & EXPERIMENTAL","Score":null,"Total":0}
引用次数: 0

Abstract

Background: Chitosan, a natural polysaccharide with known immunostimulatory potential, has shown promise in cancer therapy. However, its direct role in modulating antitumor immunity and the underlying mechanisms remain unclear. This study aimed to explore how unmodified chitosan influences tumor progression and immune responses through innate immune signaling pathways. Methods: Murine tumor models (CT26, B16-F10) were used to evaluate the antitumor effects of chitosan in vivo. Flow cytometry and histological analyses assessed changes in immune cell infiltration. Primary macrophages and gene knockout models were used to investigate the molecular mechanisms, including inflammasome activation, mitochondrial function, and hexokinase 2 (HK2) location, via ELISA, western blotting, mitochondrial assays. Results: Chitosan treatment suppressed tumor growth and metastasis, while promoting infiltration of neutrophils, monocytes, and activated T cells in the tumor microenvironment. Mechanistically, chitosan and its bioactive degradation product, N-acetylglucosamine (NAG), induced the dissociation of HK2 from mitochondria, triggering mitochondrial dysfunction, ROS overproduction, and mtDNA release. These signals jointly activated both the NLRP3 inflammasome and the cGAS-STING pathway. The antitumor effect of chitosan was attenuated in Nlrp3 -/- and Sting -/- mice, confirming the essential roles of both pathways. Conclusions: Chitosan orchestrates dual activation of NLRP3 and cGAS-STING signaling via HK2 dissociation and mitochondrial dysfunction, reprogramming the tumor immune microenvironment and enhancing antitumor immunity. These findings support chitosan's potential as a multifunctional immunoadjuvant for improving immunotherapy in resistant cancers.

壳聚糖激活NLRP3炎性体和cGAS-STING,通过己糖激酶2解离和线粒体功能障碍抑制癌症进展。
背景:壳聚糖是一种已知具有免疫刺激潜能的天然多糖,在癌症治疗中显示出前景。然而,其在调节抗肿瘤免疫中的直接作用及其潜在机制尚不清楚。本研究旨在探讨未经修饰的壳聚糖如何通过先天免疫信号通路影响肿瘤进展和免疫反应。方法:采用小鼠肿瘤模型(CT26、B16-F10)对壳聚糖的体内抗肿瘤作用进行评价。流式细胞术和组织学分析评估了免疫细胞浸润的变化。采用原代巨噬细胞和基因敲除模型,通过ELISA、western blotting和线粒体检测,研究炎症小体活化、线粒体功能和己糖激酶2 (HK2)定位等分子机制。结果:壳聚糖处理可抑制肿瘤生长和转移,同时促进肿瘤微环境中中性粒细胞、单核细胞和活化T细胞的浸润。在机制上,壳聚糖及其生物活性降解产物n -乙酰氨基葡萄糖(NAG)诱导HK2与线粒体分离,引发线粒体功能障碍、ROS过量产生和mtDNA释放。这些信号共同激活NLRP3炎性体和cGAS-STING通路。壳聚糖对Nlrp3 -/-和Sting -/-小鼠的抗肿瘤作用减弱,证实了这两种途径的重要作用。结论:壳聚糖通过HK2解离和线粒体功能障碍介导NLRP3和cGAS-STING信号的双重激活,重新编程肿瘤免疫微环境,增强抗肿瘤免疫。这些发现支持壳聚糖作为一种多功能免疫佐剂的潜力,可以改善耐药癌症的免疫治疗。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 求助全文
来源期刊
Theranostics
Theranostics MEDICINE, RESEARCH & EXPERIMENTAL-
CiteScore
25.40
自引率
1.60%
发文量
433
审稿时长
1 months
期刊介绍: Theranostics serves as a pivotal platform for the exchange of clinical and scientific insights within the diagnostic and therapeutic molecular and nanomedicine community, along with allied professions engaged in integrating molecular imaging and therapy. As a multidisciplinary journal, Theranostics showcases innovative research articles spanning fields such as in vitro diagnostics and prognostics, in vivo molecular imaging, molecular therapeutics, image-guided therapy, biosensor technology, nanobiosensors, bioelectronics, system biology, translational medicine, point-of-care applications, and personalized medicine. Encouraging a broad spectrum of biomedical research with potential theranostic applications, the journal rigorously peer-reviews primary research, alongside publishing reviews, news, and commentary that aim to bridge the gap between the laboratory, clinic, and biotechnology industries.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:604180095
Book学术官方微信