The replication stress response (RSR) involves a downstream kinase cascade comprising ataxia telangiectasia-mutated (ATM), ATM and rad3-related (ATR), checkpoint kinases 1 and 2 (CHK1/2), and WEE1-like protein kinase (WEE1), which cooperate to arrest the cell cycle, protect stalled forks, and allow time for replication fork repair. In the presence of elevated replicative stress, cancers are increasingly dependent on RSR to maintain genomic integrity. An increasing number of drug candidates targeting key RSR nodes, as monotherapy through synthetic lethality, or through rational combinations with immune checkpoint inhibitors and targeted therapies, are demonstrating promising efficacy in early phase trials. RSR targeting is also showing potential in reversing PARP inhibitor resistance, an important area of unmet clinical need. In this review, we introduce the concept of targeting the RSR, detail the current landscape of monotherapy and combination strategies, and discuss emerging therapeutic approaches, such as targeting Polθ.

复制应激反应 (RSR) 涉及下游激酶级联反应，包括共济失调毛细血管扩张症突变 (ATM)、ATM 和 rad3 相关 (ATR)、检查点激酶 1 和 2 (CHK1/2) 以及 WEE1 样蛋白激酶 (WEE1) ，它们合作阻止细胞周期，保护停滞的叉，并为复制叉的修复留出时间。在复制压力升高的情况下，癌症越来越依赖 RSR 来维持基因组完整性。越来越多的针对关键 RSR 节点的候选药物，作为通过合成杀伤力的单一疗法，或通过与免疫检查点抑制剂和靶向疗法的合理组合，在早期试验中显示出有希望的疗效。RSR 靶向也显示出逆转 PARP 抑制剂耐药性的潜力，这是一个未满足的临床需求的重要领域。在本次审查中，