Dataset Information

A DNA-Modularized STING Agonist with Macrophage-Selectivity and Programmability for Enhanced Anti-Tumor Immunotherapy.

ABSTRACT: The activation of cyclic GMP-AMP (cGAMP) synthase (cGAS) and its adaptor, stimulator of interferon genes (STING), is known to reprogram the immunosuppressive tumor microenvironment for promoting antitumor immunity. To enhance the efficiency of cGAS-STING pathway activation, macrophage-selective uptake, and programmable cytosolic release are crucial for the delivery of STING agonists. However, existing polymer- or lipid-based delivery systems encounter difficulty in integrating multiple functions meanwhile maintaining precise control and simple procedures. Herein, inspired by cGAS being a natural DNA sensor, a modularized DNA nanodevice agonist (DNDA) is designed that enable macrophage-selective uptake and programmable activation of the cGAS-STING pathway through precise self-assembly. The resulting DNA nanodevice acts as both a nanocarrier and agonist. Upon local administration, it demonstrates the ability of macrophage-selective uptake, endosomal escape, and cytosolic release of the cGAS-recognizing DNA segment, leading to robust activation of the cGAS-STING pathway and enhanced antitumor efficacy. Moreover, DNDA elicits a synergistic therapeutic effect when combined with immune checkpoint blockade. The study broadens the application of DNA nanotechnology as an immune stimulator for cGAS-STING activation.

SUBMITTER: Chen Y

PROVIDER: S-EPMC11348061 | biostudies-literature | 2024 Aug

REPOSITORIES: biostudies-literature

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A DNA-Modularized STING Agonist with Macrophage-Selectivity and Programmability for Enhanced Anti-Tumor Immunotherapy.

Chen Yingzhi Y Li Ruike R Duan Qiao Q Wu Lingling L Li Xinyi X Luo Aoxiang A Zhang Yongming Y Zhao Na N Cui Kai K Wu Wenwei W Liu Tize T Wan Jian-Bo JB Deng Liufu L Li Guiying G Hou Lijun L Tan Weihong W Xiao Zeyu Z

Advanced science (Weinheim, Baden-Wurttemberg, Germany) 20240619 32

The activation of cyclic GMP-AMP (cGAMP) synthase (cGAS) and its adaptor, stimulator of interferon genes (STING), is known to reprogram the immunosuppressive tumor microenvironment for promoting antitumor immunity. To enhance the efficiency of cGAS-STING pathway activation, macrophage-selective uptake, and programmable cytosolic release are crucial for the delivery of STING agonists. However, existing polymer- or lipid-based delivery systems encounter difficulty in integrating multiple functions ...[more]

PMID: 38898748

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Project description:IntroductionTargeting tumor vasculature is an efficient weapon to fight against cancer; however, activation of alternative pathways to rebuild the disrupted vasculature leads to rapid tumor regrowth. Immunotherapy that exploits host immune cells to elicit and sustain potent antitumor response has emerged as one of the most promising tools for cancer treatment, yet many treatments fail due to developed resistance mechanisms. Therefore, our aim was to examine whether combination of immunotherapy and anti-vascular treatment will succeed in poorly immunogenic, difficult-to-treat melanoma and triple-negative breast tumor models.MethodsOur study was performed on B16-F10 melanoma and 4T1 breast tumor murine models. Mice were treated with the stimulator of interferon genes (STING) pathway agonist (cGAMP) and vascular disrupting agent combretastatin A4 phosphate (CA4P). Tumor growth was monitored. The tumor microenvironment (TME) was comprehensively investigated using multiplex immunofluorescence and flow cytometry. We also examined if such designed therapy sensitizes investigated tumor models to an immune checkpoint inhibitor (anti-PD-1).ResultsThe use of STING agonist cGAMP as monotherapy was insufficient to effectively inhibit tumor growth due to low levels of STING protein in 4T1 tumors. However, when additionally combined with an anti-vascular agent, a significant therapeutic effect was obtained. In this model, the obtained effect was related to the TME polarization and the stimulation of the innate immune response, especially activation of NK cells. Combination therapy was unable to activate CD8+ T cells. Due to the lack of PD-1 upregulation, no improved therapeutic effect was observed when additionally combined with the anti-PD-1 inhibitor. In B16-F10 tumors, highly abundant in STING protein, cGAMP as monotherapy was sufficient to induce potent antitumor response. In this model, the therapeutic effect was due to the infiltration of the TME with activated NK cells. cGAMP also caused the infiltration of CD8+PD-1+ T cells into the TME; hence, additional benefits of using the PD-1 inhibitor were observed.ConclusionThe study provides preclinical evidence for a great influence of the TME on the outcome of applied therapy, including immune cell contribution and ICI responsiveness. We pointed the need of careful TME screening prior to antitumor treatments to achieve satisfactory results.

Dataset Information

A DNA-Modularized STING Agonist with Macrophage-Selectivity and Programmability for Enhanced Anti-Tumor Immunotherapy.

Publications

A DNA-Modularized STING Agonist with Macrophage-Selectivity and Programmability for Enhanced Anti-Tumor Immunotherapy.

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