Ma Hehua, Hong Yuxin, Xu Zhenzhen, Weng Zuyi, Yang Yuanxun, Jin Dandan, Chen Zhiyou, Zhou Xuan, Xu Zhi, Fei Fei, Song Wei, Li Juan
Phase I Clinical Trials Unit, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210008, China.
Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, 210023, China.
Sci Rep. 2025 Jan 2;15(1):55. doi: 10.1038/s41598-024-84050-7.
As immune-checkpoint inhibitors (ICIs) therapy has made great strides in hepatocellular carcinoma (HCC) treatment, improving patient response to this strategy has become the main focus of research. Accumulating evidence has shown that mA methylation plays a crucial role in the tumorigenesis and progression of HCC, while the precise impact of the mA demethylase ALKBH5 on the tumor immune microenvironment (TIME) of HCC remains poorly defined. The clinical significance of ALKBH5 and TIM3 were evaluated in human HCC tissues. The biological function of ALKBH5 was analyzed in vitro and in vivo. The HCC molecular subtypes were identified based on key ALKBH5-regulated methylation-related genes (MRGs). The differences in survival, clinical features, TIME and immunotherapy response between these two subtypes were then evaluated. The regulation of ALKBH5 on TIM3 was detected by qPCR, western blotting and MeRIP. ALKBH5 was downregulated in HCC and associated with worse prognosis. ALKBH5 inhibited the proliferation and migration activities of HCC cells in vitro and in vivo. The HCC subtype with high expression of key MRGs was characterized by immunosuppression phenotypes and a worse response to ICIs. Moreover, TIM3 was identified as a target of ALKBH5. Upregulated TIM3 level was negatively correlated with survival in HCC. The results of this study suggest that ALKBH5 is an important regulator in HCC progression. ALKBH5 exerts its influence on the TIME and immunotherapy response by targeting TIM3 in HCC. This work provides new insight into the correlation between mA modification and ICI response, which may help provide therapeutic benefits to HCC patients.
随着免疫检查点抑制剂（ICIs）疗法在肝细胞癌（HCC）治疗中取得了巨大进展，提高患者对该策略的反应已成为研究的主要焦点。越来越多的证据表明，mA甲基化在HCC的肿瘤发生和进展中起关键作用，而mA去甲基化酶ALKBH5对HCC肿瘤免疫微环境（TIME）的确切影响仍不清楚。在人类HCC组织中评估了ALKBH5和TIM3的临床意义。在体外和体内分析了ALKBH5的生物学功能。基于关键的ALKBH5调节的甲基化相关基因（MRGs）鉴定了HCC分子亚型。然后评估了这两种亚型在生存、临床特征、TIME和免疫治疗反应方面的差异。通过qPCR、蛋白质免疫印迹和MeRIP检测了ALKBH5对TIM3的调节作用。ALKBH5在HCC中表达下调，并与较差的预后相关。ALKBH5在体外和体内均抑制HCC细胞的增殖和迁移活性。关键MRGs高表达的HCC亚型具有免疫抑制表型，对ICIs的反应较差。此外，TIM3被确定为ALKBH5的靶点。TIM3水平上调与HCC患者的生存呈负相关。本研究结果表明，ALKBH5是HCC进展中的重要调节因子。ALKBH5通过靶向HCC中的TIM3对TIME和免疫治疗反应产生影响。这项工作为mA修饰与ICI反应之间的相关性提供了新的见解，这可能有助于为HCC患者提供治疗益处。
