SUMOylation, the covalent conjugation of small ubiquitin-like modifier (SUMO) proteins to protein substrates, has been reported to suppress type I interferon (IFN1) responses. TAK-981, a selective small-molecule inhibitor of SUMOylation, pharmacologically reactivates IFN1 signaling and immune responses against cancers. In vivo treatment of wild-type mice with TAK-981 up-regulated IFN1 gene expression in blood cells and splenocytes. Ex vivo treatment of mouse and human dendritic cells promoted their IFN1-dependent activation, and vaccination studies in mice demonstrated stimulation of antigen cross-presentation and T cell priming in vivo. TAK-981 also directly stimulated T cell activation, driving enhanced T cell sensitivity and response to antigen ex vivo. Consistent with these observations, TAK-981 inhibited growth of syngeneic A20 and MC38 tumors in mice, dependent upon IFN1 signaling and CD8⁺ T cells, and associated with increased intratumoral T and natural killer cell number and activation. Combination of TAK-981 with anti-PD1 or anti-CTLA4 antibodies improved the survival of mice bearing syngeneic CT26 and MC38 tumors. In conclusion, TAK-981 is a first-in-class SUMOylation inhibitor that promotes antitumor immune responses through activation of IFN1 signaling. TAK-981 is currently being studied in phase 1 clinical trials (NCT03648372, NCT04074330, NCT04776018, and NCT04381650) for the treatment of patients with solid tumors and lymphomas.

中文翻译：

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小分子 SUMOylation 抑制剂激活抗肿瘤免疫反应并增强临床前模型中的免疫治疗

据报道，SUMOylation 是小泛素样修饰剂 (SUMO) 蛋白与蛋白质底物的共价结合，可抑制 I 型干扰素 (IFN1) 反应。TAK-981 是一种选择性的 SUMO 化小分子抑制剂，可在药理学上重新激活 IFN1 信号和针对癌症的免疫反应。用 TAK-981 体内处理野生型小鼠可上调血细胞和脾细胞中的 IFN1 基因表达。小鼠和人类树突状细胞的离体治疗促进了它们依赖于 IFN1 的激活，小鼠疫苗接种研究证明了抗原交叉呈递和体内 T 细胞启动的刺激。TAK-981 还直接刺激 T 细胞活化，促进增强的 T 细胞敏感性和对离体抗原的反应。与这些观察结果一致，⁺ T 细胞，并与增加的肿瘤内 T 和自然杀伤细胞数量和激活有关。TAK-981 与抗 PD1 或抗 CTLA4 抗体的组合提高了携带同基因 CT26 和 MC38 肿瘤的小鼠的存活率。总之，TAK-981 是一流的 SUMO 化抑制剂，可通过激活 IFN1 信号传导促进抗肿瘤免疫反应。TAK-981 目前正在进行 1 期临床试验（NCT03648372、NCT04074330、NCT04776018 和 NCT04381​​650），用于治疗实体瘤和淋巴瘤患者。