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基于LPDAM平台的拉帕醌化学-光热协同疗法增强cGAS-STING激活及免疫反应用于结直肠癌治疗

Enhanced cGAS-STING Activation and Immune Response by LPDAM Platform-Based Lapachone-Chemical-Photothermal Synergistic Therapy for Colorectal Cancer.

作者信息

Pan Xiaoyu, Lin Yan, Lin Chunlin, Liu Songyi, Lin Penghang, Lin Xiang, He Ruofan, Ye ZiChen, Ye Jianxin, Zhu Guangwei

机构信息

Department of Gastrointestinal Surgery 2 Section, Institute of Abdominal Surgery, Key Laboratory of Accurate Diagnosis and Treatment of Cancer, The First Hospital Affiliated to Fujian Medical University, Fuzhou, 350005, China.

National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, China.

出版信息

Adv Healthc Mater. 2025 Apr;14(11):e2403309. doi: 10.1002/adhm.202403309. Epub 2025 Mar 19.


DOI:10.1002/adhm.202403309
PMID:40103499
Abstract

The cGAS-STING signaling pathway is a pivotal immune response mechanism that bridges tumor and immune cell interactions. This study describes a multifunctional LPDAM nanoplatform integrating Lapachone, polydopamine (PDA), and Mn, which synergistically kills tumor cells and activates the cGAS-STING pathway, thereby inducing DC maturation and T cell activation to achieve potent antitumor immunity. In the tumor microenvironment, Lapachone generates HO via the NAD(P)H:quinone oxidoreductase 1 (NQO1 enzyme), while Mn catalyze HO conversion into •OH through chemodynamic effects (CDT). The photothermal effects (PTT) of PDA further amplify this cascade reaction, producing reactive oxygen species (ROS) that damage tumor mitochondria and release mitochondrial DNA (mtDNA). The released mtDNA activates the cGAS-STING pathway, while Mn enhances the sensitivity of cGAS to mtDNA, leading to robust antitumor immunity. Concurrently, photothermal-induced immunogenic cell death (ICD) promotes dendritic cells (DCs) maturation, further strengthening immune responses. Moreover, Mn⁺ also serves as a contrast agent for T1-weighted magnetic resonance imaging (MRI), offering precise tumor visualization. This study demonstrates that the LPDAM nanoplatform facilitates Lapachone/CDT/PTT synergistic therapy under MRI guidance, showcasing its potential as an innovative strategy for combined immunotherapy in clinical oncology.

摘要

cGAS-STING信号通路是连接肿瘤与免疫细胞相互作用的关键免疫反应机制。本研究描述了一种整合了拉帕乔醌、聚多巴胺(PDA)和锰的多功能LPDAM纳米平台,该平台可协同杀死肿瘤细胞并激活cGAS-STING通路,从而诱导树突状细胞(DC)成熟和T细胞活化,以实现强大的抗肿瘤免疫。在肿瘤微环境中,拉帕乔醌通过NAD(P)H:醌氧化还原酶1(NQO1酶)产生过氧化氢(HO),而锰通过化学动力学效应(CDT)催化HO转化为羟基自由基(•OH)。PDA的光热效应(PTT)进一步放大了这一级联反应,产生活性氧(ROS),损伤肿瘤线粒体并释放线粒体DNA(mtDNA)。释放的mtDNA激活cGAS-STING通路,而锰增强cGAS对mtDNA的敏感性,从而产生强大的抗肿瘤免疫。同时,光热诱导的免疫原性细胞死亡(ICD)促进树突状细胞(DCs)成熟,进一步增强免疫反应。此外,锰离子还可作为T1加权磁共振成像(MRI)的造影剂,实现精确的肿瘤可视化。本研究表明,LPDAM纳米平台在MRI引导下促进了拉帕乔醌/CDT/PTT协同治疗,展示了其作为临床肿瘤学联合免疫治疗创新策略的潜力。

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