Nanodelivery of arsenic trioxide induces macrophage-governed cGAS-STING signaling to remodel immune microenvironment in hepatocellular carcinoma

被引：0

作者：

Li, Yuyao ^{[1
]}

Shi, Jia ^{[1
]}

Yu, Shihan ^{[1
]}

Lu, Xiaona ^{[1
]}

Li, Yue ^{[1
]}

Zheng, Wenlan ^{[1
]}

Zhang, Xuemei ^{[1
]}

Du, Wurong ^{[1
]}

Zhao, Chaoqun ^{[1
]}

Huang, Lingying ^{[1
]}

Zhu, Xiaojun ^{[1
]}

Li, Man ^{[3
]}

Wang, Lingzhi ^{[4
]}

Guo, Jianfeng ^{[4
]}

Feng, Hai ^{[2
]}

Gao, Yueqiu ^{[1
,2
]}

Yu, Zhuo ^{[1
]}

机构：

[1] Shanghai Univ Tradit Chinese Med, Shuguang Hosp Affiliated, Dept Liver Dis, Shanghai 201203, Peoples R China

[2] Shanghai Univ Tradit Chinese Med, Shuguang Hosp, Inst Infect Dis, Shanghai 201203, Peoples R China

[3] Shanghai Univ Tradit Chinese Med, Shuguang Hosp, Lab Cellular Immun, Shanghai 201203, Peoples R China

[4] Jilin Univ, Sch Pharmaceut Sci, Changchun 130021, Peoples R China

来源：

CHEMICAL ENGINEERING JOURNAL | 2025年 / 506卷

关键词：

HCC immunotherapy; Arsenic trioxide; Nanoparticle; cGAS-STING signaling; Macrophage; PATHWAY;

D O I：

10.1016/j.cej.2025.159943

中图分类号：

X [环境科学、安全科学];

学科分类号：

08 ; 0830 ;

摘要：

Hepatocellular carcinoma (HCC) responds poorly to current immunotherapies partly due to the immunosuppressive nature of tumor microenvironment (TME). The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling has emerged as a crucial cascade that stimulates immune response against tumor by remodeling the TME. Arsenic trioxide (ATO) has demonstrated cytotoxic effect on tumor cells; however, its capacity to enhance anti-HCC immunity remains poorly explored. This study aimed to investigate the mechanism by which ATO might stimulate immune response against HCC through the regulation of the cGAS-STING signaling. To achieve this purpose, we employed methodologies such as comet assay, immunoblotting, immunofluorescence, quantitative PCR, ELISA and flow cytometry, in conjunction with HCC mouse models. Our results indicated that ATO activated cGAS-STING signaling in macrophages by inducing DNA damage in HCC cells, which provoked the IFN-beta-mediated stimulation of cytotoxic CD8+ T cells. Additionally, STING activation also promoted M1 macrophage polarization, leading to increased production of immunostimulatory cytokines and chemokines. To enhance ATO-targeting delivery to tumor milieu, we developed a poly lactic-co-glycolic acid (PLGA)-based nanoparticle encapsulating ATO (ATO NP), which significantly augmented tumor suppression in HCC mouse models. Furthermore, ATO NP elicited a robust memory immune response, effectively prevented HCC recurrence, and synergistically enhanced the antitumor effect of anti-PD-1 antibody (alpha-PD-1) in mice with advanced HCC. The significance of these findings highlight the potential of ATO to activate cGAS-STING signaling, and suggest a promising HCC immunotherapeutic strategy through nanodelivery of ATO to remodel the TME.

引用

页数：16

共 49 条

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