cGAS-STING 通路的激活通过 1 型干扰素 (IFN) 的产生和 T 细胞启动，在针对癌症的先天免疫反应中发挥着关键作用。肿瘤细胞和垂死细胞内胞质双链 DNA (dsDNA) 的积累被 DNA 传感器环 GMP-AMP 合酶 (cGAS) 识别，产生第二信使 cGAMP，进而激活 STING（干扰素基因的 ST 刺激器），从而产生干扰素相关基因的后续表达。该过程由三素修复核酸外切酶 1 (TREX1) 调节，TREX1 是一种 3' → 5' 核酸外切酶，可降解胞质 dsDNA，从而抑制 cGAS-STING 途径的激活，进而减少免疫刺激性 IFN 的分泌。在这里，我们表征了 VB-85680 的活性，VB-85680 是一种有效的 TREX1 小分子抑制剂。我们首先证明 VB-85680 在体外抑制人类和小鼠细胞系裂解物中的 TREX1 核酸外切酶活性。然后，我们证明用 VB-85680 处理完整细胞会激活下游 STING 信号传导，并激活 IFN 刺激基因 (ISG)。当用 VB-85680 与外源 DNA 结合处理时，在低血清条件下培养的 THP1-Dual™ 细胞表现出增强的 ISG 反应。总的来说，这些发现表明 TREX1 核酸外切酶抑制剂与产生胞质 DNA 的药物联合使用的潜力，可增强与 STING 通路激活广泛相关的抗肿瘤免疫的获得。版权所有：© 2024 Flowers 等人。这是一篇根据知识共享署名许可条款分发的开放获取文章，允许在任何媒体上不受限制地使用、分发和复制，前提是注明原始作者和来源。

Activation of the cGAS-STING pathway plays a key role in the innate immune response to cancer through Type-1 Interferon (IFN) production and T cell priming. Accumulation of cytosolic double-stranded DNA (dsDNA) within tumor cells and dying cells is recognized by the DNA sensor cyclic GMP-AMP synthase (cGAS) to create the secondary messenger cGAMP, which in turn activates STING (STimulator of INterferon Genes), resulting in the subsequent expression of IFN-related genes. This process is regulated by Three-prime Repair EXonuclease 1 (TREX1), a 3' → 5' exonuclease that degrades cytosolic dsDNA, thereby dampening activation of the cGAS-STING pathway, which in turn diminishes immunostimulatory IFN secretion. Here, we characterize the activity of VB-85680, a potent small-molecule inhibitor of TREX1. We first demonstrate that VB-85680 inhibits TREX1 exonuclease activity in vitro in lysates from both human and mouse cell lines. We then show that treatment of intact cells with VB-85680 results in activation of downstream STING signaling, and activation of IFN-stimulated genes (ISGs). THP1-Dual™ cells cultured under low-serum conditions exhibited an enhanced ISG response when treated with VB-85680 in combination with exogenous DNA. Collectively, these findings suggest the potential of a TREX1 exonuclease inhibitor to work in combination with agents that generate cytosolic DNA to enhance the acquisition of the anti-tumor immunity widely associated with STING pathway activation.Copyright: © 2024 Flowers et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.