葡萄糖传感器NSUN2-m5C修饰调节瘤免疫葡萄糖代谢重编程,以驱动肝细胞癌的进化
Jing He1,2,3,4,5, Boqiang Liu1,2,3,4,5, Weijun Zhao1,2,3,4,5
1Zhejiang Provincial Key Laboratory of Laparoscopic Technology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, 310016, China.
瘤进化通过改变葡萄糖代谢和免疫细胞功能来驱动抵抗. 通过PD-L1阻断准葡萄糖代谢和NSUN2,为肝细胞癌 (HCC) 提供了一种新的策略.
科学领域:
- 在瘤学瘤学.
- 免疫学 免疫学 免疫学
- 代谢途径 代谢途径
背景情况:
- 瘤异质性和不断发展的免疫微环境 (TIME) 驱动治疗耐药性和肝细胞癌 (HCC) 等癌症的不良预后.
- 了解瘤进化和免疫反应之间的动态相互作用对于开发有效的治疗方法至关重要.
研究的目的:
- 阐明 HCC.中瘤进化和免疫微环境动态背后的机制.
- 为了确定关键的基因和代谢变化驱动瘤进展和治疗耐药性.
- 开发和评估一种新的双重向治疗策略,用于治疗耐药的HCC.
主要方法:
- 建立了一种小鼠瘤进化模型 (TEM) 来识别进化核心基因.
- 开发了一种单细胞TEM,使用HCC临床标本和外部队列进行动态瘤免疫相互作用分析.
- 研究了葡萄糖代谢模式和NSUN2在瘤细胞和CD8+T细胞在瘤进化过程中的作用.
主要成果:
- 在瘤进化过程中确定了恶性细胞和CD8+ T细胞之间对比的葡萄糖代谢模式.
- 发现瘤细胞中的NSUN2上调,由葡萄糖代谢主导,通过mRNA甲基化稳定糖溶性转录 (GLUT1,HK2,PFKM).
- 证明NSUN2介导的GLUT1稳定增强瘤细胞的葡萄糖获取,加速恶性瘤和损害CD8+T细胞功能.
- 表明,在临床前模型中,将GLUT1/NSUN2抑制剂 (WZB117) 与PD-L1阻断相结合的双重向策略协同抑制了瘤进化并逆转了免疫抑制.
结论:
- 瘤细胞利用NSUN2上调的葡萄糖代谢获得竞争优势,导致免疫抑制和HCC的治疗耐药性.
- 针对GLUT1/NSUN2轴和PD-L1阻塞的组合疗法是克服HCC治疗耐药性的有希望的协同策略.
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