高纤维结缔间质是晚期胰腺癌产生化疗抵抗的重要原因之一，而其形成与TGF-β刺激胰腺星状细胞（PSCs）活化密切相关。本项目首次提出“间质重塑-化疗增敏”的联合治疗策略，即针对PSCs表面过度表达纤维细胞激活蛋白α（FAPα），设计FAPα生物响应型PSCs靶向制剂，将TGF-β受体激酶抑制剂高效靶向递送至PSCs并响应释药，从而有效抑制PSCs活化，下调间质结缔组织增生；在重塑微环境基础上序贯联用临床化疗制剂，可显著提高胰腺癌化疗效果。本项目将系统考察PSCs靶向制剂理化性质，通过二维细胞模型、壳-核结构3D细胞球模型和原位荷瘤动物模型系统评价PSCs靶向性及对微环境重塑能力，并建立该制剂和化疗制剂序贯治疗方案，考察化疗敏感性，并在微环境表征基础上阐明化疗增敏机制，为建立安全、高效的晚期胰腺癌联合治疗方案提供实验基础和理论依据，对提高富含间质实体瘤的临床治疗水平具有重要理论意义和应用价值。

Pancreatic cancer (PC) is one of the most aggressive tumors with a high mortality rate and short survival. The high resistance of advanced PC to conventional chemotherapy treatments is one of the principal reason for the poor prognosis. The enriched stroma of PC is believed to be an important contributing factor to the poor therapeutic response. The pancreatic stellate cells (PSCs) activated by transforming growth factor-β (TGF-β) are thought to play a crucial role in the formation of enriched stroma microenvironment. In this study, a novel sequential combination therapy strategy was put forward to increase the treatment of advanced PC, i.e., “remodeling the tumor microenvironment by a PSCs-targeting nanopreparation, followed by chemotherapy with higher sensitivity”. PSCs exhibit high expression of fibroblast activation protein α (FAPα) on the surface. Therefore, a FAPα-responsive nanopreparation for PSCs-specific targeting was developed to delivery TGF-β receptor inhibitor, galunisertib, which could efficiently inhibit the activation of PSCs and down-regulate the interstitial fibrosis in the stroma. On the base of the remodeled tumor microenvironment induced by the PSCs-targeting nanopreparation, a conventional chemotherapy was sequentially performed and an increased anti-tumor efficiency was achieved. In this study, PSCs-targeting nanopreparation was prepared and the physicochemical properties were studied in detail. Moreover, the PSCs targeting abilities and the capacity of remodeling the stroma microenvironment were studied using two-dimensional cell model, three-dimensional cell ball model with core-shell structure and orthotopic tumor models. The sequential combination of PSCs-targeting nanopreparation and conventional chemotherapy were performed to on orthotopic tumor models, and the anti-tumor efficiency and safety were observed. Moreover, the mechanism of increased sensitivity of PC to chemotherapy was explored by charactering the tumor microenvironment. This sequential combination therapy strategy will provide an efficient and promising mean for the advanced PC treatment，which also has important significance for the effective treatment of other stroma-rich solid tumors.