Xing Cong, Tu Xintao, Huai Wanwan, Tang Zhen, Song Kun, Jeltema Devon, Knox Kennady, Dobbs Nicole, Yang Kun, Yan Nan
Department of Immunology, UT Southwestern Medical Center, Dallas, Texas.
Cancer Res. 2025 Aug 1;85(15):2858-2875. doi: 10.1158/0008-5472.CAN-24-2747.
Three-prime repair exonuclease 1 (TREX1) is the major DNase in mammalian cells that degrades cytosolic DNA to prevent activation of the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway. Genotoxic stress, DNA damage, and radiotherapy induce TREX1 expression in cancer cells, allowing them to evade innate immune activation of type I IFN-mediated antitumor response. Therefore, targeting TREX1 could represent a potential approach to stimulate antitumor immunity. In this study, we conducted a high-throughput small-molecule inhibitor screen of TREX1 using a cell-free DNase assay. Compound 296 specifically inhibited TREX1 DNase activity at low micromolar concentrations, induced type I IFN signaling in cancer cells, and inhibited tumor growth in mice in an inteferon alpha/beta receptor (IFNAR)-dependent manner. Treatment with compound 296 also stimulated T-cell infiltration into tumors and synergized with immune checkpoint blockade. Trex1 knockout cancer cells elicited robust systemic antitumor immunity through tumor-intrinsic cGAS-STING activation and functioned as autologous cancer vaccines that protected against tumor challenge and metastasis. An inducible whole-body Trex1 knockout mouse model was established to simulate "on-demand" systemic TREX1 inactivation in adult mice. Sustained TREX1 loss suppressed a broad range of solid and metastatic tumors in adult mice without incurring severe immune toxicity, even when combined with immune checkpoint blockade, demonstrating the feasibility of an immune-safe therapeutic window. Together, these data demonstrate the antitumor efficacy and immune safety of multiple therapeutic modalities targeting TREX1, including targeting small-molecule inhibitors of TREX1 and employing TREX1 knockout tumor cells as an autologous cancer vaccine. These approaches should pave the way for developing TREX1-targeted cancer immunotherapies.
Therapeutic modalities targeting TREX1 can activate cGAS-STING signaling and can be incorporated into autologous cancer vaccine designs to improve cancer treatment, supporting the potential of inactivating TREX1 to harness innate immunity. See related commentary by Hanks, p. 2778.
3'-修复外切核酸酶1（TREX1）是哺乳动物细胞中的主要脱氧核糖核酸酶，可降解胞质DNA以防止环磷酸鸟苷-腺苷酸合成酶（cGAS）-干扰素基因刺激因子（STING）途径的激活。基因毒性应激、DNA损伤和放射疗法可诱导癌细胞中TREX1的表达，使其能够逃避I型干扰素介导的抗肿瘤反应的先天免疫激活。因此，靶向TREX1可能是一种刺激抗肿瘤免疫的潜在方法。在本研究中，我们使用无细胞脱氧核糖核酸酶测定法对TREX1进行了高通量小分子抑制剂筛选。化合物296在低微摩尔浓度下特异性抑制TREX1脱氧核糖核酸酶活性，诱导癌细胞中的I型干扰素信号传导，并以干扰素α/β受体（IFNAR）依赖性方式抑制小鼠肿瘤生长。用化合物296治疗还可刺激T细胞浸润肿瘤，并与免疫检查点阻断协同作用。Trex1基因敲除癌细胞通过肿瘤内在的cGAS-STING激活引发强大的全身抗肿瘤免疫，并作为自体癌症疫苗发挥作用，可预防肿瘤攻击和转移。建立了一种可诱导的全身Trex1基因敲除小鼠模型，以模拟成年小鼠中“按需”的全身TREX1失活。持续的TREX1缺失可抑制成年小鼠中的多种实体瘤和转移性肿瘤，而不会产生严重的免疫毒性，即使与免疫检查点阻断联合使用也是如此，这证明了免疫安全治疗窗口的可行性。总之，这些数据证明了多种靶向TREX1的治疗方式的抗肿瘤疗效和免疫安全性，包括靶向TREX1的小分子抑制剂以及将TREX1基因敲除肿瘤细胞用作自体癌症疫苗。这些方法应为开发靶向TREX1的癌症免疫疗法铺平道路。
靶向TREX1的治疗方式可激活cGAS-STING信号传导，并可纳入自体癌症疫苗设计中以改善癌症治疗，支持失活TREX1以利用先天免疫的潜力。见Hanks的相关评论，第2778页。
