Inhibitory Microenvironment Remodeling Enhances STING Activation for Solid Tumor Immunotherapy,Advanced Functional Materials

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Inhibitory Microenvironment Remodeling Enhances STING Activation for Solid Tumor Immunotherapy
Advanced Functional Materials ( IF 18.5 ) Pub Date : 2025-02-21 , DOI: 10.1002/adfm.202421849
Wenming Fang _{1,

2} , Lizhu Chen ₃ , Ping Hu _{1,

4} , Jianlin Shi _{1,

2,

4}

Affiliation

The immunomodulatory effect of the interferon gene‐stimulating factor (STING) pathway makes it an important target for tumor immunotherapy, which, however, suffers from the easy degradation and deteriorated stimulatory capacity of current STING agonists in the solid tumor microenvironment. Herein, a nanocomposite medicine， MLAP， is constructed by intercalating STING agonist ADU‐S100 into Mn‐doped layered double hydroxide, which is capable of modulating the immune microenvironment of solid tumors to enhance STING activation. Importantly, the intercalation in the interlayer structure enhances the intracellular permeability of STING agonists, meanwhile, the activation of the STING pathway by ADU‐S100 is amplified by the sensitizing effect of Mn2+. In addition, the moderate alkalinity of MLAP neutralizes the acidity of the tumor microenvironment and catalyzes the decomposition of hydrogen peroxide to produce oxygen, rectifying the acidic and hypoxia immunosuppressive microenvironment and thus strengthening the immune activation efficacy of STING agonists. This work provides an excellent carrier for STING agonists, which not only improves the bioavailability of STING agonists but also remodels the immune microenvironment for boosted solid tumor immunotherapy.

中文翻译：

抑制性微环境重塑增强实体瘤免疫治疗的 STING 激活

干扰素基因刺激因子（STING）通路的免疫调节作用使其成为肿瘤免疫治疗的重要靶点，然而，目前 STING 激动剂在实体瘤微环境中容易降解和刺激能力下降。在此，通过将 STING 激动剂 ADU-S100 嵌入 Mn 掺杂的层状双氢氧化物中构建了一种纳米复合药物 MLAP，其能够调节实体瘤的免疫微环境以增强 STING 激活。重要的是，层间结构中的嵌入增强了 STING 激动剂的细胞内通透性，同时，ADU-S100 对 STING 通路的激活被 Mn2+ 的致敏作用放大。此外，MLAP 的中等碱性中和了肿瘤微环境的酸性，催化过氧化氢分解产生氧气，纠正了酸性缺氧的免疫抑制微环境，从而加强了 STING 激动剂的免疫激活功效。这项工作为 STING 激动剂提供了极好的载体，不仅提高了 STING 激动剂的生物利用度，还重塑了增强实体瘤免疫治疗的免疫微环境。

更新日期：2025-02-21

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