有丝分裂 MTH1 抑制剂 TH1579 是一种双重抑制剂，可抑制有丝分裂和氧化 DNA 损伤的掺入，并导致癌症特异性细胞死亡。 DNA 损伤剂通常通过 cGAS-STING 途径增强对免疫检查点抑制剂 (ICI) 治疗的反应。本研究探讨 TH1579 是否可以通过其免疫调节特性提高免疫检查点阻断的功效。用有丝分裂的 MTH1i TH1579 处理各种人和小鼠癌细胞系，并通过流式细胞术和实时 qPCR 分析 PD-L1 和 T 细胞浸润相关趋化因子的表达。建立同基因小鼠模型来检查 TH1579 和 PD-L1 阻断的联合效应。在我们的研究中，我们发现 TH1579 上调人类癌细胞系中蛋白质和 mRNA 水平的 PD-L1 表达。然而，在小鼠细胞系中，这种增加不太明显。同基因小鼠黑色素瘤模型的体内实验表明，与媒介物或 atezolizumab 单一疗法相比，TH1579 治疗显着提高了 atezolizumab（一种抗 PD-L1 抗体）的疗效。此外，TH1579 表现出免疫调节特性，以 cGAS-STING 通路依赖性方式升高 IFN-β 等细胞因子以及 CCL5 和 CXCL10 等趋化因子。总之，TH1579 有潜力通过调节免疫检查点相关蛋白和通路来改善 ICI 治疗。© 2024。作者。

The mitotic MTH1 inhibitor TH1579 is a dual inhibitor that inhibits mitosis and incorporation of oxidative DNA damage and leads to cancer-specific cell death. The response to immune checkpoint inhibitor (ICI) treatment is often augmented by DNA damaging agents through the cGAS-STING pathway. This study investigates whether TH1579 can improve the efficacy of immune checkpoint blockades through its immunomodulatory properties. Various human and murine cancer cell lines were treated with mitotic MTH1i TH1579, and the expression of PD-L1 and T-cell infiltration-related chemokines was analysed by flow cytometry and real-time qPCR. Syngeneic mouse models were established to examine the combined effect of TH1579 and PD-L1 blockade. In our investigation, we found that TH1579 upregulates PD-L1 expression at both the protein and mRNA levels in human cancer cell lines. However, in murine cell lines, the increase was less pronounced. An in vivo experiment in a syngeneic mouse melanoma model showed that TH1579 treatment significantly increased the efficacy of atezolizumab, an anti-PD-L1 antibody, compared to vehicle or atezolizumab monotherapy. Furthermore, TH1579 exhibited immune-modulatory properties, elevating cytokines such as IFN-β and chemokines including CCL5 and CXCL10, in a cGAS-STING pathway-dependent manner. In conclusion, TH1579 has the potential to improve ICI treatment by modulating immune checkpoint-related proteins and pathways.© 2024. The Author(s).