Trex1 m6A去甲基化修饰在肝癌放疗诱导的抗肿瘤免疫效应中的作用及其机制研究

放疗是原发性肝癌（简称肝癌）的主要治疗手段，但放疗后复发率较高。近年来研究证实，放疗后肿瘤细胞产生的双链DNA碎片激活树突状细胞（DCs）内cGAS-STING通路，是增强其抗肿瘤免疫效应的关键。然而，辐射剂量达到一定阈值会激活核酸酶Trex1，降解细胞质中双链DNA，从而削弱抗肿瘤免疫效应，其调控机制尚不清楚。我们前期研究发现，DCs受照射后，会促进m6A去甲基化酶ALKBH5的表达，而ALKBH5通过对Trex1 mRNA去甲基化，下调其mRNA表达。因此，我们提出假说，放疗通过ALKBH5对Trex1 mRNA去甲基化增强cGAS-STING通路的活化，增强放疗诱导的抗肿瘤免疫效应。本课题拟从细胞、动物以及临床等不同层次，从m6A甲基化新角度阐明ALKBH5与放疗诱导的cGAS-STING通路活化之间的关系和分子机制，为增强肝癌放疗诱导的抗肿瘤免疫效应提供新的干预策略。

Radiotherapy (RT) is the primary treatment for primary liver cancer. But the recurrence rate is relatively high after RT. Previous studies had confirmed that double-stranded DNA (dsDNA) from tumor cells upon radiation could activate the cGAS-STING signaling pathway in dendritic cells (DCs), which is the key to enhance radiation-induced antitumor immunity. When tumor treated with a dose of radiation above the threshold for Trex1, Trex1 will activate and degrade dsDNA that accumulates in the cytosol, which in turn attenuate the radiation-driven radiation-induced antitumor immunity. However, how IR regulating Trex1 remains unclear. We previously found that the m6A demethylase ALKBH5 was upregulated in DCs after RT. Besides, ALKBH5 would regulate Trex1 mRNA demethylation and downregulate Trex1 mRNA and then activate the cGAS-STING signaling pathway. Based on these observations, we hypothesized that ALKBH5 may promote Trex1 mRNA demethylation, then activate the cGAS-STING signaling pathway and finally enhance radiation-induced antitumor immunity. This project is intended to use the cells, animals, and clinical samples to provide a new prospective from mRNA m6A methylation to elucidate the relationship and mechanism between ALKBH5 and the activation of cGAS-STING pathway induced by RT and may offer a targeting point for the enhancement of radiation-induced antitumor immunity.