PARP7 is a monoPARP that catalyzes the transfer of single units of ADP-ribose onto substrates to change their function. Here, we identify PARP7 as a negative regulator of nucleic acid sensing in tumor cells. Inhibition of PARP7 restores type I interferon (IFN) signaling responses to nucleic acids in tumor models. Restored signaling can directly inhibit cell proliferation and activate the immune system, both of which contribute to tumor regression. Oral dosing of the PARP7 small-molecule inhibitor, RBN-2397, results in complete tumor regression in a lung cancer xenograft and induces tumor-specific adaptive immune memory in an immunocompetent mouse cancer model, dependent on inducing type I IFN signaling in tumor cells. PARP7 is a therapeutic target whose inhibition induces both cancer cell-autonomous and immune stimulatory effects via enhanced IFN signaling. These data support the targeting of a monoPARP in cancer and introduce a potent and selective PARP7 inhibitor to enter clinical development.

PARP7 是一种 monoPARP，可催化单个单元的 ADP-核糖转移到底物上以改变其功能。在这里，我们将 PARP7 鉴定为肿瘤细胞中核酸感应的负调节因子。在肿瘤模型中，PARP7 的抑制恢复了对核酸的 I 型干扰素 (IFN) 信号反应。恢复的信号可以直接抑制细胞增殖并激活免疫系统，这两者都有助于肿瘤消退。PARP7 小分子抑制剂 RBN-2397 的口服给药导致肺癌异种移植物中的肿瘤完全消退，并在免疫活性小鼠癌症模型中诱导肿瘤特异性适应性免疫记忆，这取决于在肿瘤细胞中诱导 I 型干扰素信号。PARP7 是一种治疗靶点，其抑制作用通过增强的 IFN 信号传导诱导癌细胞自主和免疫刺激作用。这些数据支持在癌症中靶向 monoPARP，并引入有效的选择性 PARP7 抑制剂进入临床开发。