PIK3R3是PI3K调节亚基家族的重要成员之一，在细胞的生长信号通路中扮演重要角色，文献报道其与肿瘤发生、进展密切相关。我们前期研究证实PIK3R3过表达是胰腺癌不良预后的独立危险因素。在系列功能实验和深度测序及分析的基础上，我们提出“胰腺癌细胞异常高表达的PIK3R3通过磷酸化通路激活BCL-3/p50/IL10信号轴诱导NK 细胞失能及杀伤活性下降”的假说。本项目拟通过CHIP实验、Co-IP实验、回复实验，基因工程鼠模型的构建，特异性PIK3R3抑制短肽的使用等系列体内外实验手段，证实上述信号轴在胰腺癌免疫逃逸中的作用，验证阻断该信号轴对于改善胰腺癌预后的效应，旨在证明PIK3R3在胰腺癌中作用新机制的同时，为基于PIK3R3、NK细胞的胰腺癌免疫治疗提供了潜在靶点及理论依据。

PIK3R3 is a the PI3K regulatory subunit which plays an important role in the cell growth signaling pathway. It has been reported that PIK3R3 is significantly associated with the progression of some tumors. Our previous study confirmed that PIK3R3 overexpression is an independent risk factor for poor prognosis of pancreatic cancer. Based on the results of functional assays and deep sequencing, we hypothesize that overexpression of PIK3R3 in pancreatic cancer cells may activate BCL-3/p50/IL10 signaling axis via phosphorylation pathways, and further induce NK cell dysfunction and cytotoxicity decreasing. This project intends to confirm the role of above-mentioned signal axis in pancreatic cancer immune escape, and to verify the effect of blocking the signal axis on improving pancreatic cancer prognosis via several in vitro and in vivo assays, such as CHIP assay, Co-IP assay, related rescue assay, genetically engineered mice model, and specific PIK3R3 inhibitory short peptide application in this model. This project aims to demonstrate a new mechanism of PIK3R3 in pancreatic cancer and provide a potential target and theoretical basis for immunotherapy of pancreatic cancer based on PIK3R3 and NK cells.