DNA损伤反应（DDR）缺陷已成为近年来治疗乳腺癌的新兴靶点之一。一方面，DDR协调细胞周期和信号转导，其功能障碍可能导致细胞凋亡、基因组不稳定和肿瘤发展。相反，DDR 缺陷是肿瘤的一个内在特征，是肿瘤对造成 DNA 损伤的治疗做出反应的基础。在这篇综述中，我们系统地探讨了DDR的各种机制、DDR靶向药物治疗乳腺癌的原理和研究进展，并讨论了其临床应用中的挑战。值得注意的是，聚（ADP-核糖）聚合酶（PARP）抑制剂在一系列临床试验中已证明对具有高同质重组缺陷（HRD）状态的乳腺癌具有良好的疗效和安全性。此外，一些关于新型 DDR 相关分子的研究正在积极探索针对对 PARP 抑制产生抗性的肿瘤。在新疗法或药物进一步临床应用之前，需要开发新颖且标准化的生物标志物，以准确描述受益人群的特征并预测疗效。尽管 DDR 相关治疗的疗效有希望，但脱靶毒性和耐药性的挑战仍需解决。克服耐药性的策略有待对DDR机制的进一步探索，联合靶向药物或免疫治疗将有望提供更精确或联合的策略，并扩大潜在的反应人群。©2024。作者。

DNA damage response (DDR) deficiency has been one of the emerging targets in treating breast cancer in recent years. On the one hand, DDR coordinates cell cycle and signal transduction, whose dysfunction may lead to cell apoptosis, genomic instability, and tumor development. Conversely, DDR deficiency is an intrinsic feature of tumors that underlies their response to treatments that inflict DNA damage. In this review, we systematically explore various mechanisms of DDR, the rationale and research advances in DDR-targeted drugs in breast cancer, and discuss the challenges in its clinical applications. Notably, poly (ADP-ribose) polymerase (PARP) inhibitors have demonstrated favorable efficacy and safety in breast cancer with high homogenous recombination deficiency (HRD) status in a series of clinical trials. Moreover, several studies on novel DDR-related molecules are actively exploring to target tumors that become resistant to PARP inhibition. Before further clinical application of new regimens or drugs, novel and standardized biomarkers are needed to develop for accurately characterizing the benefit population and predicting efficacy. Despite the promising efficacy of DDR-related treatments, challenges of off-target toxicity and drug resistance need to be addressed. Strategies to overcome drug resistance await further exploration on DDR mechanisms, and combined targeted drugs or immunotherapy will hopefully provide more precise or combined strategies and expand potential responsive populations.© 2024. The Author(s).