多聚腺苷酸核苷酸聚合酶（PARP）抑制剂（PARPi）已经显示出治疗BRCA缺陷肿瘤的巨大潜力。但是，超过40％的BRCA缺陷患者对PARPi无反应。在这里，我们报告了一种下一代PARPi，即thioparib，对PARPi敏感和耐药的具有同源重组（HR）缺陷的细胞在体内外均表现出高的抗肿瘤活性，包括针对多种PARP，包括PARP1，PARP2和PARP7的高亲和力。 Thioparib治疗引起了PARP1依赖的DNA损伤和复制应激，引起S期停滞和凋亡。相反，thioparib强烈抑制了HR介导的DNA修复，并增加了RAD51成核点形成。值得注意的是，thioparib通过靶向抑制PARP7，激活STING / TBK1依赖的STAT1磷酸化，在免疫复合小鼠模型中触发了I型干扰素（IFNs）的强烈诱导，并导致肿瘤生长延缓。然而，thioparib对肿瘤生长的抑制作用在PARP1敲除小鼠中更为显著，这表明相对于thioparib这种全谱抑制剂，特异性PARP7抑制剂更为适用于临床应用。最后，基因组规模的CRISPR筛选确定了PARP1和MCRS1作为能够调节thioparib敏感性的基因。总之，thioparib作为同时作用于DNA损伤应答和抗肿瘤免疫的下一代PARPi，为治疗高活性HR肿瘤，包括早期PARPi耐药肿瘤提供了治疗潜力。 ©2023作者。根据CC BY 4.0许可证条款发表。

Poly-ADP-ribose polymerase (PARP) inhibitors (PARPi) have shown great promise for treating BRCA-deficient tumors. However, over 40% of BRCA-deficient patients fail to respond to PARPi. Here, we report that thioparib, a next-generation PARPi with high affinity against multiple PARPs, including PARP1, PARP2, and PARP7, displays high antitumor activities against PARPi-sensitive and -resistant cells with homologous recombination (HR) deficiency both in vitro and in vivo. Thioparib treatment elicited PARP1-dependent DNA damage and replication stress, causing S-phase arrest and apoptosis. Conversely, thioparib strongly inhibited HR-mediated DNA repair while increasing RAD51 foci formation. Notably, the on-target inhibition of PARP7 by thioparib-activated STING/TBK1-dependent phosphorylation of STAT1, triggered a strong induction of type I interferons (IFNs), and resulted in tumor growth retardation in an immunocompetent mouse model. However, the inhibitory effect of thioparib on tumor growth was more pronounced in PARP1 knockout mice, suggesting that a specific PARP7 inhibitor, rather than a pan inhibitor such as thioparib, would be more relevant for clinical applications. Finally, genome-scale CRISPR screening identified PARP1 and MCRS1 as genes capable of modulating thioparib sensitivity. Taken together, thioparib, a next-generation PARPi acting on both DNA damage response and antitumor immunity, serves as a therapeutic potential for treating hyperactive HR tumors, including those resistant to earlier-generation PARPi.© 2023 The Authors. Published under the terms of the CC BY 4.0 license.