多基因异常是肿瘤发生的主要驱动因素。 NF-κB p65 过度激活和 cGAS 沉默是加速肿瘤发生的重要触发因素和遗传缺陷。然而，同时纠正 NF-κB p65 和 cGAS 异常仍有待进一步探索。在这里，我们提出了一种新的诱导双靶点再平衡（IDTR）策略，用于同时纠正 cGAS 和 NF-κB p65 中的缺陷。通过使用IDTR方法，我们首次证明溶瘤腺病毒H101可以重新激活沉默的cGAS，同时沉默GAU1长非编码RNA（lncRNA）抑制NF-κB p65过度激活，从而在结直肠肿瘤中产生有效的体外和体内抗肿瘤功效。有趣的是，我们进一步证明溶瘤腺病毒通过促进 cGAS 启动子的 H3K4 三甲基化来重新激活 cGAS。此外，使用反义寡核苷酸沉默 GAU1 可显着降低 NF-κB p65 启动子处的 H3K27 乙酰化，并抑制 NF-κB p65 转录。我们的研究揭示了两种肿瘤缺陷（cGAS 和 NF-κB p65）背后的异常治疗机制，并提供了一种基于溶瘤腺病毒和反义寡核苷酸的替代 IDTR 方法，以实现肿瘤的有效治疗效果。© 2024。作者。

Multiple gene abnormalities are major drivers of tumorigenesis. NF-κB p65 overactivation and cGAS silencing are important triggers and genetic defects that accelerate tumorigenesis. However, the simultaneous correction of NF-κB p65 and cGAS abnormalities remains to be further explored. Here, we propose a novel Induced Dual-Target Rebalance (IDTR) strategy for simultaneously correcting defects in cGAS and NF-κB p65. By using our IDTR approach, we showed for the first time that oncolytic adenovirus H101 could reactivate silenced cGAS, while silencing GAU1 long noncoding RNA (lncRNA) inhibited NF-κB p65 overactivation, resulting in efficient in vitro and in vivo antitumor efficacy in colorectal tumors. Intriguingly, we further demonstrated that oncolytic adenoviruses reactivated cGAS by promoting H3K4 trimethylation of the cGAS promoter. In addition, silencing GAU1 using antisense oligonucleotides significantly reduced H3K27 acetylation at the NF-κB p65 promoter and inhibited NF-κB p65 transcription. Our study revealed an aberrant therapeutic mechanism underlying two tumor defects, cGAS and NF-κB p65, and provided an alternative IDTR approach based on oncolytic adenovirus and antisense oligonucleotides for efficient therapeutic efficacy in tumors.© 2024. The Author(s).