免疫抑制是 HCC 肿瘤微环境的特征，最近的研究表明 RNA 结合蛋白 (RBP) 与 HCC 的发展有关。在这里，我们进行了筛选，并确定 RBM12 是增加 PD-L1 表达的关键蛋白，从而驱动 HCC 的免疫逃避。此外，RBM12被发现在HCC组织中显着上调，并且与HCC患者的不良预后相关。通过各种分子测定和高通量筛选，我们确定RBM12可以通过其第4-RRM（RNA识别基序）结构域直接结合JAK1 mRNA，并通过其第2-RRM结构域招募EIF4A2，从而增强核糖体在JAK1 mRNA上的分布，促进 JAK1 的翻译及其表达的随后上调。因此，激活的 JAK1/STAT1 通路转录上调 PD-L1 表达，促进 HCC 的免疫逃避。总之，我们的研究结果提供了关于 RBM12 对 HCC 免疫逃避的重大贡献的见解，突显了其作为未来治疗靶点的潜力。该图解摘要表明，HCC 中 RBM12 的表达升高可以通过提高 JAK1 mRNA 翻译的效率来增强 PD-L1 介导的肿瘤免疫逃避。© 2024。作者，获得 Springer Nature Limited 的独家许可。

Immunosuppression characterizes the tumour microenvironment in HCC, and recent studies have implicated RNA-binding proteins (RBPs) in the development of HCC. Here, we conducted a screen and identified RBM12 as a key protein that increased the expression of PD-L1, thereby driving immune evasion in HCC. Furthermore, RBM12 was found to be significantly upregulated in HCC tissues and was associated with a poor prognosis for HCC patients. Through various molecular assays and high-throughput screening, we determined that RBM12 could directly bind to the JAK1 mRNA via its 4th-RRM (RNA recognition motif) domain and recruit EIF4A2 through its 2nd-RRM domain, enhancing the distribution of ribosomes on JAK1 mRNA, which promotes the translation of JAK1 and the subsequent upregulation of its expression. As a result, the activated JAK1/STAT1 pathway transcriptionally upregulates PD-L1 expression, facilitating immune evasion in HCC. In summary, our findings provide insights into the significant contribution of RBM12 to immune evasion in HCC, highlighting its potential as a therapeutic target in the future. This graphical abstract shows that elevated expression of RBM12 in HCC can augment PD-L1-mediated tumour immune evasion by increasing the efficiency of JAK1 mRNA translation.© 2024. The Author(s), under exclusive licence to Springer Nature Limited.