Aurora-A通过阻断磷脂酰乙醇胺生成抑制铁死亡介导肝细胞癌免疫逃逸的机制研究

免疫治疗是多种晚期肿瘤的新兴治疗手段，但在肝癌患者中疗效欠佳。Aurora-A是导致肿瘤细胞免疫逃逸的关键分子，预实验发现它可导致PE生成减少和肝癌细胞铁死亡不足。PE是诱导癌细胞铁死亡的重要物质，而铁死亡不足正是免疫逃逸的重要成因。PE生成依赖于线粒体-内质网膜（MAM）结构。Drp-1介导的过度线粒体分裂可减少MAM形成，而Aurora-A又可增强Drp-1功能。综上，我们提出以下科学问题：1. Aurora-A是否在肝癌的免疫应答中发挥关键作用；2.下调PE抑制铁死亡是否是Aurora-A调控肝癌免疫应答的主要机制；3.Aurora-A是否通过调控Drp-1磷酸化导致线粒体分裂增加，MAM减少，从而影响PE的合成；4.Aurora-A是否可以作为预测肝癌病人免疫治疗疗效的标志物。围绕科学问题，本项目将阐明肝癌免疫逃逸新机制，为疗效预测及改进临床治疗方案提供更多思路。

As an emerging treatment for many advanced cancers, immunotherapy is unsatisfactory in patients with hepatocellular carcinoma (HCC). Aurora-A is a key molecule that contributes to tumor immune escape. We found that Aurora-A can reduce the production of PE, leading to insufficient ferroptosis in HCC. PE has been demonstrated to promote ferroptosis in cancer cells, which can enhance the effect of immunotherapy. PE production depends on a structure called mitochondria associated ER membrans (MAM), which can be reduced by the Drp-1 mediated mitochondrial fission, while Aurora-A can enhance the activity of Drp-1. Accordingly, we raise the following scientific questions: 1. Whether Aurora-A plays a key role in the immune response of HCC; 2. Whether down regulation of PE and inhibition of ferroptosis is the primary mechanism of Aurora-A mediated immune escape of HCC; 3. Whether Aurora-A can affect the synthesis of PE by regulating the phosphorylation of Drp-1, increasing the mitochondrial fission and reducing MAM formantion; 4. Whether Aurora-A can be used as a biomarker to predict the efficacy of immunotherapy in HCC patients. Focusing on these scientific issues, this project will clarify the new mechanisms of immune escape of HCC, to provide more evidence for prediction and improvement of the effect of immunotherapy.