PARP7已被证明在免疫中发挥重要作用。在多种癌细胞类型中观察到 PARP7 显着上调，从而导致 Ⅰ 型干扰素信号通路受到抑制。因此，抑制PARP7的活性可以增强Ⅰ型干扰素信号传导，从而发挥抗肿瘤免疫反应。在这项研究中，我们报告了一种新发现的 PARP7 抑制剂 (XLY-1)，其抑制活性 (IC50 = 0.6 nM) 高于 RBN-2397 (IC50 = 6.0 nM)。此外，XYL-1 对 PARP1 表现出弱抑制活性 (IC50 > 1.0 μM)。机制研究表明，XYL-1可以在体外增强Ⅰ型干扰素信号传导。药效实验表明，50 mg/kg XYL-1可显着抑制肿瘤生长（TGI：76.5%），相关实验表明，XYL-1可恢复Ⅰ型干扰素信号传导，促进肿瘤组织中T细胞浸润。总而言之，XYL-1 显示出作为开发癌症免疫治疗药物的潜在候选者的前景。版权所有 © 2024 Elsevier Inc. 保留所有权利。

PARP7 has been proven to play an important role in immunity. Substantial upregulation of PARP7 is observed in numerous cancerous cell types, consequently resulting in the inhibition of type Ⅰ interferon signaling pathways. Therefore, inhibiting the activity of PARP7 can enhance type Ⅰ interferon signaling to exert an anti-tumor immune response. In this study, we reported the identification of a newly found PARP7 inhibitor (XLY-1) with higher inhibitory activity (IC50 = 0.6 nM) than that of RBN-2397 (IC50 = 6.0 nM). Additionally, XYL-1 displayed weak inhibitory activity on PARP1 (IC50 > 1.0 μM). Mechanism studies showed that XYL-1 could enhance the type Ⅰ interferon signaling in vitro. Pharmacodynamic experiments showed that 50 mg/kg XYL-1 could significantly inhibit tumor growth (TGI: 76.5 %) and related experiments showed that XYL-1 could restore type Ⅰ interferon signaling and promote T cell infiltration in tumor tissues. Taken together, XYL-1 shows promise as a potential candidate for developing cancer immunotherapy agents.Copyright © 2024 Elsevier Inc. All rights reserved.