A dual-STING-activating nanosystem expands cancer immunotherapeutic temporal window.

IF 11.7 1区医学 Q1 CELL BIOLOGY

Cell Reports Medicine Pub Date : 2024-10-17 DOI:10.1016/j.xcrm.2024.101797

Jian Wang, Xiaohu Wang, Qingqing Xiong, Shan Gao, Shihao Wang, Siqi Zhu, Shuting Xiang, Mingxi Li, Haitang Xie, Suxin Li

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引用次数: 0

Abstract

Stimulator of interferon genes (STING) is a promising antitumor target via bridging innate and adaptive immunity, yet the transient nature of immune signal transduction renders small-molecule agonists susceptible to short time effectiveness. Here, we report a dual-STING-activating micelle system (D-SAM) to dynamically program STING kinetics. Mechanistically, the natural ligand cGAMP encapsulated in D-SAM initiates STING signaling, while the pH-sensitive polymeric agonist PC7A disassembled from micelle shell buffers lysosomal protons and retards STING degradation. This prolonged STING activity facilitates dendritic cell (DC) antigen presentation and extends cytotoxic T lymphocyte priming. D-SAM improves efficacy over single soluble or delivered agonists against established, metastatic, and recurring murine tumors. Specific depletion of STING in DCs or blockade of CD8⁺ T cell infiltration abrogates therapeutic effects. The feasibility of immune modulation is further validated in resected human patient tissues. This work underscores the temporal rhythm of STING as crucial for mounting a potent and enduring antitumor immune response.

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双 STING 激活纳米系统拓展了癌症免疫治疗的时间窗口。

干扰素基因刺激器（STING）是连接先天性免疫和适应性免疫的一个很有前景的抗肿瘤靶点，然而免疫信号转导的瞬时性使小分子激动剂容易在短时间内失效。在这里，我们报告了一种可动态编程 STING 动力学的双 STING 激活胶束系统（D-SAM）。从机理上讲，封装在 D-SAM 中的天然配体 cGAMP 启动了 STING 信号转导，而从胶束外壳中分解出的 pH 敏感性聚合激动剂 PC7A 则缓冲溶酶体质子并延缓 STING 降解。STING 活性的延长有利于树突状细胞（DC）的抗原呈递，并延长细胞毒性 T 淋巴细胞的启动时间。与单一的可溶性或递送激动剂相比，D-SAM 提高了对已确诊、转移和复发小鼠肿瘤的疗效。特异性消耗 DC 中的 STING 或阻断 CD8+ T 细胞浸润会减弱治疗效果。免疫调节的可行性在切除的人体患者组织中得到了进一步验证。这项研究强调了 STING 的时间节律对于产生有效而持久的抗肿瘤免疫反应至关重要。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cell Reports Medicine Biochemistry, Genetics and Molecular Biology-Biochemistry, Genetics and Molecular Biology (all)

CiteScore

15.00

自引率

1.40%

发文量

231

审稿时长

40 days

期刊介绍： Cell Reports Medicine is an esteemed open-access journal by Cell Press that publishes groundbreaking research in translational and clinical biomedical sciences, influencing human health and medicine. Our journal ensures wide visibility and accessibility, reaching scientists and clinicians across various medical disciplines. We publish original research that spans from intriguing human biology concepts to all aspects of clinical work. We encourage submissions that introduce innovative ideas, forging new paths in clinical research and practice. We also welcome studies that provide vital information, enhancing our understanding of current standards of care in diagnosis, treatment, and prognosis. This encompasses translational studies, clinical trials (including long-term follow-ups), genomics, biomarker discovery, and technological advancements that contribute to diagnostics, treatment, and healthcare. Additionally, studies based on vertebrate model organisms are within the scope of the journal, as long as they directly relate to human health and disease.