聚（ADP-核糖）聚合酶抑制剂（PARPis）因其合成的致死相互作用而被批准用于癌症治疗，并且临床试验已应用于非小细胞肺癌。然而，PARPis 对肺腺癌（LUAD）的治疗效果仍不清楚。我们探讨了突变的视网膜母细胞瘤基因 (RB1) 对 LUAD 中 PARPi 敏感性的影响。进行生物信息学筛选以确定 PARPi 敏感的生物标志物。在这里，我们发现 PARPis（niraparib、rucaparib 和 olaparib）显着降低了 RB1 突变的 LUAD 细胞系的活力。 RB1缺陷引起基因组不稳定，促进胞质双链DNA（dsDNA）形成，激活cGAS/STING通路，并上调下游趋化因子CCL5和CXCL10，引发免疫细胞浸润。异种移植实验表明 PARPi 治疗可减少 RB1-KO 小鼠的肿瘤发生。此外，单细胞RNA测序分析表明，RB1表达下调的恶性细胞与其他细胞类型有更多的交流，表现出特定信号传导的激活，例如GAS、IFN反应、抗原呈递和细胞因子活性。我们的研究结果表明，RB1 突变通过触发 cGAS/STING 通路和上调 LUAD 中的免疫浸润，通过合成致死效应介导对 PARPis 的敏感性，这可能是一种潜在的治疗策略。

Poly (ADP-ribose) polymerase inhibitors (PARPis) are approved for cancer therapy according to their synthetic lethal interactions, and clinical trials have been applied in non-small cell lung cancer. However, the therapeutic efficacy of PARPis in lung adenocarcinoma (LUAD) is still unknown. We explored the effect of a mutated retinoblastoma gene (RB1) on PARPi sensitivity in LUAD. Bioinformatic screening was performed to identify PARPi-sensitive biomarkers. Here, we showed that viability of LUAD cell lines with mutated RB1 was significantly decreased by PARPis (niraparib, rucaparib, and olaparib). RB1 deficiency induced genomic instability, prompted cytosolic double-stranded DNA (dsDNA) formation, activated the cGAS/STING pathway, and upregulated downstream chemokines CCL5 and CXCL10, triggering immune cell infiltration. Xenograft experiments indicated that PARPi treatment reduced tumorigenesis in RB1-KO mice. Additionally, single-cell RNA sequencing analysis showed that malignant cells with downregulated expression of RB1 had more communications with other cell types, exhibiting activation of specific signaling such as GAS, IFN response, and antigen-presenting and cytokine activities. Our findings suggest that RB1 mutation mediates the sensitivity to PARPis through a synthetic lethal effect by triggering the cGAS/STING pathway and upregulation of immune infiltration in LUAD, which may be a potential therapeutic strategy.