血管生成抑制剂联合免疫治疗因具有良好的协同抗肿瘤作用而备受关注，其中以肿瘤微环境为基础的血管正常化诱导和免疫检查点抑制剂介入治疗的剂量和时间窗以及活体疗效的精准动态评估等问题是困扰其进一步临床应用的主要障碍。本项目拟在课题组前期成功应用多模式MRI活体定量监测肿瘤血管靶向药物治疗疗效及其机制的基础上，进一步从肿瘤在体微环境的血流动力学、乏氧、pH三个角度对血管生成抑制剂Bevacizumab诱导的血管正常化及其联合CTLA-4免疫靶向治疗过程进行全面、动态、精准的可视化监测与分析，同时结合PCR、Western blot、免疫组织化学以及流式细胞分析等方法，从分子、细胞、动物模型多个层面探讨联合序贯治疗作用机制，构建有效的影像学生物标记物，期望能据此指导用药时间窗和剂量，确定序贯治疗方案，为肿瘤诊疗的分子功能可视化应用提供科学依据。

The angiogenesis inhibitors in combination with immunotherapy has drawn much attentions due to its good synergistic anti-tumor effect. How to validate the dosage and “the window of opportunity” of vascular normalization induction and immunological checkpoint inhibitor intervention based on tumor microenvironment and accurately assess the dynamic anti-tumor effect of the combination therapy in vivo have have hindered its further clinical application. Previously, we have successfully assessed the anti-tumor therapy and mechanism of vascular-targeting agents in vivo using multimodal MRI. Here, with the application of multimodal imaging, we intend to precisely analyze the vascular normalization induced by angiogenesis inhibitor Bevacizumab and comprehensively monitor the dynamic anti-tumor effect of the combination therapy with CTLA-4 immunological checkpoint inhibitor from the aspects of tumor microenvironment in hemodynamics, hypoxia and pH. Furthermore, combined with the PCR, western blot, flow cytometry and immunohistochemistry, we are able to explore the mechanism of the sequential therapy from the molecular, cellar and animal model levels, and establish effective image biomarker to guide the induced dosage and “the window of opportunity” of vascular normalization and determine the sequential therapy scheme combined with immunological checkpoint inhibitor, providing the new scientific evidences for the further application of molecular visualization in cancer diagnosis and treatment.