基因组不稳定性被确认为癌症的一种基本特征。DNA损伤应答（DDR）网络负责维持细胞的基因组完整性。由于癌细胞经常携带DDR基因缺陷或遭受复制应激，靶向DDR过程可能会导致过多的DNA损伤（或未修复的DNA），最终导致细胞死亡。PARP（聚合酶poly (ADP-ribose) polymerase）抑制剂已经为带有乳腺癌基因（BRCA）突变或同源重组缺陷（HRD）的患者带来了显著的益处，这证实了癌症治疗中的合成致死概念。此外，在复制应激和与化疗或放疗结合的另外两种DDR抑制剂应用方案下，正在积极进行临床研究。在本综述中，我们重新审视了除首代PARP抑制剂以外的DDR靶向治疗研究进展。下一代PARP1选择性抑制剂在减轻副作用的同时维持了其有效性，可能会扩大PARP抑制剂在临床中的应用范围。尽管存在必然的靶点毒性，几种靶向DNA损伤检查站的小分子抑制剂在初步临床结果中表现出极大的潜力，值得进一步评估。此外，其他DNA修复途径（放守者）的抑制剂也在积极进行临床前或临床研究开发。随着这些进展和努力，我们预见DDR领域的新一波创新已经成熟。© 2023. 四川大学华西医院。

Genome instability has been identified as one of the enabling hallmarks in cancer. DNA damage response (DDR) network is responsible for maintenance of genome integrity in cells. As cancer cells frequently carry DDR gene deficiencies or suffer from replicative stress, targeting DDR processes could induce excessive DNA damages (or unrepaired DNA) that eventually lead to cell death. Poly (ADP-ribose) polymerase (PARP) inhibitors have brought impressive benefit to patients with breast cancer gene (BRCA) mutation or homologous recombination deficiency (HRD), which proves the concept of synthetic lethality in cancer treatment. Moreover, the other two scenarios of DDR inhibitor application, replication stress and combination with chemo- or radio- therapy, are under active clinical exploration. In this review, we revisited the progress of DDR targeting therapy beyond the launched first-generation PARP inhibitors. Next generation PARP1 selective inhibitors, which could maintain the efficacy while mitigating side effects, may diversify the application scenarios of PARP inhibitor in clinic. Albeit with unavoidable on-mechanism toxicities, several small molecules targeting DNA damage checkpoints (gatekeepers) have shown great promise in preliminary clinical results, which may warrant further evaluations. In addition, inhibitors for other DNA repair pathways (caretakers) are also under active preclinical or clinical development. With these progresses and efforts, we envision that a new wave of innovations within DDR has come of age.© 2023. West China Hospital, Sichuan University.