Hepatocellular carcinoma (HCC) is a malignant tumor characterized by rapid progression. To explore the regulatory mechanism of rapid tumor growth and metastasis, we conducted proteomic and scRNA-Seq analyses on advanced HCC tissues and identified a significant molecule, guanine monophosphate synthase (GMPS), closely associated with the immune evasion in HCC. We analyzed the immune microenvironment characteristics remodeled by GMPS using scRNA-Seq and found GMPS induced tumor immune evasion in HCC by impairing the tumor-killing function of CD8 ⁺ T cells. Further investigation revealed that GMPS increased PD-L1 expression by regulating its ubiquitination and glycosylation modification. Mechanistically, GMPS enhanced the bond between PD-L1 and the catalytic subunit STT3A of oligosaccharyltransferase (OST) by acting as an additional module connecting the Sec61 channel complex and STT3A, which aided in the translocation and modification of nascent peptides. Increased PD-L1 impaired the tumor-killing function of CD8 ⁺ T cells, leading to the immune evasion. Importantly, targeting GMPS with angustmycin A, an inhibitor of GMPS activity, significantly suppressed PD-L1 expression and tumor growth in HCC, which also increased the sensitivity to anti-CTLA-4 immunotherapy. These findings suggested the potential of targeting GMPS as a promising therapeutic approach for HCC.

肝细胞癌 （HCC） 是一种以快速进展为特征的恶性肿瘤。为了探索肿瘤快速生长和转移的调控机制，我们对晚期 HCC 组织进行了蛋白质组学和 scRNA-Seq 分析，并鉴定出一个与 HCC 免疫逃避密切相关的重要分子鸟嘌呤单磷酸合酶 （GMPS）。我们使用 scRNA-Seq 分析了 GMPS 重塑的免疫微环境特征，发现 GMPS 通过损害 CD8 ⁺ T 细胞的肿瘤杀伤功能诱导 HCC 中的肿瘤免疫逃逸。进一步研究显示，GMPS 通过调节其泛素化和糖基化修饰来增加 PD-L1 的表达。从机制上讲，GMPS 通过充当连接 Sec61 通道复合物和 STT3A 的附加模块来增强 PD-L1 与寡糖基转移酶 （OST） 催化亚基 STT3A 之间的结合，这有助于新生肽的易位和修饰。PD-L1 升高损害了 CD8 ⁺ T 细胞的肿瘤杀伤功能，导致免疫逃逸。重要的是，用 GMPS 活性抑制剂安古斯特霉素 A 靶向 GMPS 显着抑制了 HCC 中 PD-L1 的表达和肿瘤生长，这也增加了对抗 CTLA-4 免疫疗法的敏感性。这些发现表明靶向 GMPS 作为 HCC 的有前途的治疗方法的潜力。