胰腺癌早期诊断率较低，进展极快，5年生存率仅为6-8%。目前认为，多种途径诱导的免疫逃逸是胰腺癌早期浸润转移的重要原因，但机制不明。本课题研究目标是阐明胰腺癌外泌体通过调控未折叠蛋白反应（p38-JUN通路调控的内质网未折叠蛋白反应和SOD2调控的线粒体未折叠蛋白反应）导致肿瘤免疫逃逸的分子机制，并探索T细胞内源性关键基因阻滞技术。本课题拟通过CytOF技术和小鼠胰腺癌淋巴结转移模型研究外泌体对T细胞表型和细胞因子分泌的影响；通过蛋白质组学、蛋白质乙酰化组学和cas9干扰技术明确T细胞内质网未折叠蛋白反应和线粒体未折叠蛋白反应的分子机制；通过外泌体RNA干扰技术阻断T细胞p38/SOD2表达，激活抗肿瘤免疫。研究结果有助于更深入地了解胰腺癌外泌体在肿瘤微环境中的免疫调控功能，对胰腺癌的精准免疫治疗技术的发展具有重要意义，也具有良好的临床转化和应用前景。

Pancreatic cancer is one of the most aggressive cancer and is associated with low rate of early diagnosis. The 5-year relative survival rate for patients with all clinical stages of pancreatic cancer combined is 6-8%. It was reported that multi-pathway induced immune escape was an important reason for early invasion and metastasis of pancreatic cancer, however, the mechanism of immune escape was not clear. Our project is aim to elucidate the mechanism of tumor immune escape modulated by pancreatic cancer derived exosome through regulating unfolded protein response（UPR）of T cells, and to explore the endogenous key gene blocking technique of T cells. In this study, the effects of pancreatic cancer derived exosomes on T cell phenotype and cytokine secretion will be studied by using CytOF technology and mouse lymph node metastasis model of pancreatic cancer; the mechanism of MTUPR of T cells will be specified through proteomics, protein acetylationomics and cas9 interference technology; Exosome RNA interference technology will be used to block the expression of p38 and SOD2 in T cells and activate anti-tumor immunity. This study is of great significance to elucidate the mechanism of exosome-induced immune escape in pancreatic cancer, to the development of precision immunotherapy technology for pancreatic cancer.