肿瘤细胞治疗研究
英文原题：Metabolic Reprogramming of NSUN2-Mediated m(5)C Modification Promotes the Progression of Hepatocellular Carcinoma by Restricting Natural Killer Cell-Mediated Cytotoxicity.
Metabolic Reprogramming of NSUN2-Mediated m(5)C Modification Promotes the Progression of Hepatocellular Carcinoma by Restricting Natural Killer Cell-Mediated Cytotoxicity.
这些发现提示，NSUN2 可能是 m5C RNA 甲基化与免疫抑制之间的关键枢纽，为 HCC 的联合免疫治疗提供了治疗依据。
背景：肝细胞癌（HCC）仍是癌症相关死亡的主要原因之一，其对免疫治疗的耐药构成了重大临床挑战。自然杀伤（NK）细胞在HCC中表现出浸润和细胞毒性受损；然而，NK细胞介导的免疫逃逸机制仍知之甚少。本研究探讨了NOP2/Sun RNA甲基转移酶2（NSUN2），一种5-甲基胞嘧啶（m5C）RNA甲基转移酶，如何诱导代谢重编程和免疫抑制以驱动HCC进展。方法：我们在与NK细胞共培养的HCC细胞中进行了全基因组CRISPR筛选。为阐明下游机制，我们将m5C表观转录组、转录组和染色质景观分析与代谢特征相结合。进一步研究了NSUN2对组蛋白乳酸化和程序性细胞死亡1配体1（PD-L1）转录的影响。使用同系小鼠模型和药理抑制的体外和体内功能实验验证了这些发现。使用患者组织、癌症基因组图谱数据集和免疫治疗队列评估了临床相关性。结果：在HCC细胞-NK细胞共培养模型中的全基因组CRISPR筛选确定NSUN2是NK细胞介导的细胞毒性的关键抑制因子。机制上，NSUN2介导的RNA m5C修饰增强了糖酵解酶的mRNA稳定性和表达，包括烯醇化酶1（ENO1）、丙酮酸激酶M1/2（PKM）和乳酸脱氢酶A（LDHA），从而增加乳酸产生。累积的乳酸促进了组蛋白 H3 第 18 位赖氨酸乳酰化（H3K18la），从而增强了 CD274（编码 PD-L1）启动子处的染色质可及性，并招募信号转导与转录激活因子 3（STAT3）驱动 PD-L1 表达，最终抑制 NK 细胞介导的细胞毒性。在临床上，NSUN2 高表达与 HCC 患者 PD-L1 水平升高、预后不良及免疫治疗耐药相关。在体内，敲除 NSUN2 可增加 NK 细胞浸润并抑制肿瘤生长，而 STAT3 抑制剂 TTI-101 联合 anti-PD-L1 治疗可增强 NK 细胞细胞毒性并抑制 HCC 进展。结论：我们的数据表明，NSUN2 通过将 m5C 依赖的糖酵解重编程与 H3K18la 介导的 PD-L1 表观遗传激活相偶联，驱动了 HCC 的免疫逃逸。这些发现提示，NSUN2 可能代表 m5C RNA 甲基化与免疫抑制之间的关键枢纽，为 HCC 的联合免疫治疗提供了治疗依据。
Background: Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality, with resistance to immunotherapy posing a major clinical challenge. Natural killer (NK) cells exhibit impaired infiltration and cytotoxicity in HCC; however, the mechanisms underlying NK cell-mediated immune evasion are still poorly understood. This study investigated how NOP2/Sun RNA methyltransferase 2 (NSUN2), a 5-methylcytosine (m 5 C) RNA methyltransferase, induces metabolic reprogramming and immunosuppression to drive HCC progression. Methods: We conducted a genome-wide CRISPR screen in HCC cells cocultured with NK cells. To delineate the downstream mechanisms, we integrated profiling of the m5C epitranscriptome, transcriptome, and chromatin landscape with metabolic characterization. The impact of NSUN2 on histone lactylation and programmed cell death 1 ligand 1 (PD-L1) transcription was further investigated. Functional assays in vitro and in vivo using syngeneic murine models and pharmacological inhibition validated these findings. Clinical relevance was assessed using patient tissues, The Cancer Genome Atlas dataset, and immunotherapy cohorts. Results: Genome-wide CRISPR screening in HCC cell-NK cell coculture models identified NSUN2 as a key suppressor of NK cell-mediated cytotoxicity. Mechanistically, NSUN2-mediated RNA m 5 C modification enhanced the messenger RNA stability and expression of glycolytic enzymes, including enolase 1 ( ENO1 ), pyruvate kinase M1/2 ( PKM ), and lactate dehydrogenase A ( LDHA ), thereby increasing lactate production. Accumulated lactate promoted histone H3 lysine 18 lactylation (H3K18la), which enhanced chromatin accessibility at the CD274 (encoding PD-L1) promoter and recruited signal transducer and activator of transcription 3 (STAT3) to drive PD-L1 expression, ultimately inhibiting NK cell-mediated cytotoxicity. Clinically, high NSUN2 expression was associated with elevated PD-L1 levels, poor prognosis, and immunotherapy resistance in patients with HCC. In vivo, NSUN2 knockout increased NK cell infiltration and suppressed tumor growth, while the STAT3 inhibitor TTI-101 combined with anti-PD-L1 therapy enhanced NK cell cytotoxicity and inhibited HCC progression. Conclusions: Our data demonstrated that NSUN2 drove immune evasion in HCC by coupling m 5 C-dependent glycolytic reprogramming with H3K18la-mediated epigenetic activation of PD-L1. These findings suggest that NSUN2 could represent a critical nexus between m 5 C RNA methylation and immunosuppression, providing a therapeutic rationale for combination immunotherapy in HCC.
MEMBER ACCOUNT
登录成功会直接打开下一页。
