癌相关成纤维细胞
肿瘤微环境
免疫系统
癌症研究
基质
免疫疗法
肝细胞癌
癌症免疫疗法
化学
生物
免疫学
免疫组织化学
作者
Chuanchen Wu,Yuantao Mao,Fanghui Zhang,Xin Wang,Nannan Fan,Wen Zhang,Wei Zhang,Ping Li,Bo Tang
标识
DOI:10.1016/j.snb.2023.133891
摘要
Tumor microenvironment (TME) promotes the immune evasion hindering the hepatocellular carcinoma (HCC) immunotherapy. Cancer-associated fibroblasts (CAFs) as dominant stroma cells in the TME play critical roles in the immune evasion of HCC. However, the underlying molecular mechanism remains unclear. Herein, we construct an in-situ fluorescence imaging strategy to monitor the dynamic activation and distribution of CAFs, which is associated with a near-infrared (NIR) fluorescence probe Cy-FAP. This probe consists of cyanine derivative and valine-proline dipeptide responsive toward fibroblast activation protein-α (FAP), a biomarker of CAFs. Based on intramolecular charge transfer (ICT), after FAP cutting off the dipeptide specifically, fluorescence intensity at 705 nm enhances significantly. Through in vivo imaging with Cy-FAP, we revealed that the FAP expression was positively related to the immune evasion of HCC. Subsequently, we found that the JAK2 of CAFs was oxidized by the excessively generated ROS, resulting in the down-regulation of TNF-α and INF-γ and up-regulation of PD-L1. These led to exhaustion of CD8+ T cells and further enhanced the immune evasion of HCC. In conclusion, the real-time and in-situ monitoring of CAFs established here provides a powerful tool for exploring the roles of CAFs in the development of HCC.
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