免疫抑制微环境是导致肿瘤细胞免疫逃逸和侵袭转移的重要因素。Smad2和PD-L1分别激活TGF-β/Smad和PD-1/PD-L1信号通路而诱导免疫抑制微环境。课题组前期研究发现：胰腺癌中miR-148a-3p可靶向调控Smad2和PD-L1，同时环状RNA46523异常表达上调并可能作为miRNA海绵吸附miR-148a-3p。故推测胰腺癌中存在环状RNA46523-miR-148a-3p-Smad2/PD-L1调控轴持续上调Smad2/PD-L1的表达，激活相关信号通路，介导肿瘤免疫抑制微环境，促进侵袭转移。本项目首先分析该调控轴中各分子在胰腺癌组织中表达的相关性及其与肿瘤免疫微环境的关系，然后经体外实验干预调控轴中各分子的表达，明确其上下游调控关系及其对胰腺癌恶行性的影响，最后经免疫健全小鼠胰腺原位移植瘤实验进一步体内验证。研究结果有望为重塑胰腺癌免疫微环境的靶向治疗提供新的切入点。

The immunosuppressive microenvironment is an important promoting factor for the immune evasion and metastases of cancer cells. Smad2 and PD-L1 can induce immunosuppressive microenvironment through activating TGF-β/Smad and PD-1/PD-L1 signaling pathways, respectively. Our previous studies indicated that Smad2 and PD-L1 were two direct targets of miR-148a-3p in pancreatic cancer. Meanwhile, hsa_circ_0046523 was aberrantly upregulation and could function as a miRNA sponge of miR-148a-3p. Therefore, we hypothesize there may be an hsa_circ_0046523-miR-148a-3p-Smad2/PD-L1 regulating axis in pancreatic cancer. This regulating axis might continuously upregulate Smad2 and PD-L1 expression, activate TGF-β/Smad and PD-1/PD-L1 signaling pathways which result in the induction of tumor immunosuppressive microenvironment, and promote invasion and metastases in pancreatic cancer. To test this hypothesis, we plan to evaluate the gene expression and their interactions of this hsa_circ_0046523-miR-148a-3p-Smad2/PD-L1 regulating axis in pancreatic cancer. The effects of introduction of immunosuppressive microenvironment through hsa_circ_0046523-miR-148a-3p-Smad2/PD-L1 regulating axis will also be evaluated in vitro and in vivo, as well as their regulatory relationships. The study might provide novel therapeutic targets for the treatment of pancreatic cancer through remodeling tumor immune microenvironment.