丝氨酸代谢介导AUF1 m6A RNA修饰抑制代谢检查点MAT2A重塑胶质瘤免疫抑制微环境

以代谢重编程为基础的肿瘤免疫抑制微环境是肿瘤免疫治疗抵抗的根源。近期研究表明丝氨酸与RNA甲基化有关，胶质瘤具有选择摄取丝氨酸的特性，但丝氨酸代谢在胶质瘤m6A修饰、胶质瘤免疫抑制微环境（GIME）和胶质瘤免疫治疗中的作用尚待确认。申请者前期研究发现剥夺丝氨酸可诱导胶质瘤相关巨噬细胞M1型转化，这与RNA结合蛋白AUF1抑制代谢检查点MAT2A表达有关，同时还发现限制胶质瘤丝氨酸代谢可抑制AUF1 m6A修饰，因此提出假说：干扰丝氨酸代谢可通过下调AUF1 m6A修饰抑制MAT2A表达重塑GIME。我们拟运用MeRIP-seq等明确丝氨酸代谢调控AUF1 m6A修饰的机制；深入探索AUF1 m6A修饰调控MAT2A重塑GIME的机制；利用团队筛选出具有高血脑屏障透过率的溶瘤病毒探索MAT2A的临床转化潜力，为明确胶质瘤中丝氨酸代谢与m6A修饰、GIME的关系以及胶质瘤免疫治疗提供新的思路。

Tumor immunotherapy resistance is induced by tumor immunosuppressive microenvironment which is maintained by metabolic reprogramming. Recently, increasing studies have proved that serine is vital for RNA methylation, and glioma has the character of selectively utilizing serine, however, the crosstalk between serine metabolic reprogramming and glioma cell m6A RNA methylation, glioma immunosuppressive microenvironment (GIME), glioma immunotherapy remain unclear. Our previous experiments have found that disturbing serine metabolism could induce glioma associated macrophages subtype M1 polarization, it is related to the suppressive expression of metabolic checkpoint MAT2A which was regulated by RNA binding protein AUF1. Meanwhile, we found that serine deprivation could suppress AUF1 m6A RNA methylation. Above all we hypothesize that AUF1 m6A RNA methylation mediated by serine metabolism reprogramming could remodel GIME by inhibiting metabolic checkpoint MAT2A. This study aim to exploring the mechanism of serine metabolism reprogramming regulates AUF1 m6A RNA methylation by MeRIP-seq, further demonstrated the mechanism by which AUF1 m6A RNA methylation regulates MAT2A and remodels GIME, clarifying the clinical transformation potential of MAT2A via oncolytic viruses with high blood-brain barrier permeability, this study will facilitate to provide a novel strategy for clarifying the relationship between serine metabolism and m6A modification, GIME, immunotherapy in glioma.