我们前期研究发现局部RAS存在于肿瘤乏氧微环境中，局部RAS阻断不仅抑制了正常免疫小鼠乳腺癌的生长而且显著改善了免疫检查点治疗的效果；结合RAS在介导慢性器官损害中的机制，我们推测肿瘤内局部RAS可能介导了肿瘤内免疫抑制性微环境的形成。在此，我们利用自发性小鼠乳腺癌和4T1小鼠乳腺癌同源移植瘤模型及人乳腺癌样本，拟研究：1）局部RAS存在于乳腺癌乏氧微环境的特性及产生的机制；2）局部RAS促进乳腺癌免疫抑制性微环境形成及促进肿瘤免疫逃逸的功能；3）局部RAS介导肿瘤相关成纤维细胞（CAFs）和肿瘤相关巨噬细胞(TAMs)浸润及功能活化的作用及机制；4）局部RAS调节CAFs和TAMs之间相互作用的功能及机制；5）局部RAS阻断改善抗肿瘤免疫及提高免疫检查点阻断疗效的作用。本项目将揭示介导肿瘤免疫抑制性微环境形成的重要机制，对于改进当前免疫治疗策略以及寻找新的免疫治疗手段具有十分重要的意义。

In our previous study on tumor microenvironment, we have found, for the first time, that local renin-angiotensin system (RAS) was activated in tumor hypoxia microenvironment, and that the blocker of RAS signal remarkably inhibited tumour growth in mice with completive immune system and even remarkably improved effects of immunological checkpoint antagonists on breast cancer in mice. According to the mechanism of RAS-mediated chronic organ damage, here , untilizing the MMTV-PyMT transgenic breast cancer mouse model, mouse 4T1 breast cancer cells, and human breast cancer cells, we try to reveal: 1） an important function and the mechanism of activation of local RAS in hypoxia microenvironment of breast cancer; 2) the role of tumour local RAS in formation of immunosuppressive microenvironment in breast cancer; 3) the role and molecular mechanism of tumour local RAS in the infiltration and activation of cancer-associated fibroblasts (CAFs) and tumor-associated macrophages (TAMs) in tumour microenvironment of breast cancer; 4) the role of local RAS in regulating interaction between CAFs and TAMs in tumour microenvironment of breast cancer; 5) the contribution of local RAS inhibition by Ang II receptor blockers to the anti-tumor effects of immunological checkpoint antagonists. Our study will probably reveal an important mechanism mediating the formation of immunosuppressive microenvironment in breast cancer and bring a more positive impact on improving effect of anti-tumor immunotherapy.