靶向FAP的超声纳米微泡重构肿瘤间质增敏抗PD-1治疗及机制研究

PD-1抑制剂抗肿瘤疗效显著，但总体应答率偏低。因此，研究新的免疫疗法和联合治疗策略是当前肿瘤治疗研究的热点。本项目是在前期发现超声激励成纤维激活蛋白（FAP）靶向的载声敏剂纳米微泡降低瘤内的癌相关成纤维细胞（CAFs）并显著抗肿瘤生长的基础上，首先研究其对Lewis肺癌和MC38结肠癌小鼠移植瘤组织内CAFs的死亡或远离激活表型、肿瘤血管正常化以及CD8+T细胞抗肿瘤免疫反应的影响。随后，采用微流控芯片肿瘤与基质细胞共培养模型，研究通过靶向FAP信号清除CAFs促进肿瘤间质重构诱导血管正常化并增强CD8+T细胞浸润和活化的分子机制。最后采用人肺癌类器官和人源化小鼠模型验证其与PD-1单抗联用的治疗效能。阐明超声纳米微泡抗CAFs介导的血管生成和免疫逃逸作用及机理，确定新的声免疫疗法和联合治疗策略具有重要理论意义和潜在临床应用价值。

PD-1 inhibitors have demonstrated remarkable efficacy in a wide range of advanced cancers, but the overall response rate is low. Therefore, the research on novel targets and combination therapy strategies is currently a hot spot. Our previous work demonstrates that the nanobubbles mediated fibroblast-activation protein (FAP) targeted sonoimmunotherapy (FAP-IR-780-NBs-SIT) efficiently eliminate tumor-associated fibroblasts (CAFs), and promote infiltration of cytotoxic T cells and inhibit tumor growth in the mice bearing Lewis lung cancer. We first investigate the effects of FAP-IR-780-NBs-SIT on the elimination or inactivation of CAFs and their expression of immunosuppressive molecules, and normalization of tumor vessels and anti-tumor immune response of CD8+ T cells in mouse Lewis lung cancer and MC38 colonic cancer. Subsequently, tumor-stroma cell co-culture in a microfluidic chip are used to study whether FAP-targeted ultrasound nanobubbles reduce CAF-mediated vascular abnormalities and CD8+ T cell inability and depletion through the inactivation of fibroblasts and downregulation of their expression of immunosuppressive molecules via targeting inhibition of FAP signaling. Finally, the efficacy of the combination with PD-1 inhibitors is tested in the humanized lung cancer mouse model. Together, FAP-targeted ultrasound nanobubbles prevent CAF-mediated immunosuppression and angiogenesis and improve anti-PD-1 therapy, and may serve as a potential combination therapy strategy in human cancer, and thus have important theoretical significance and clinical value.