Targeting Pin1 to overcome immunosuppressive tumor microenvironment in MSS colorectal cancer

作者：Jian Wang, Shuxin Tang, Jinhua Fan, Huihui Xiao, Shihua Wang, Jianqin Xiang, Zhili Liu, Hongying Liu, Zhigang Pei, Dequan Jiang, Lu Shuai, Han Liu, Jian Ye, Jianli Xu, Chengyuan Qian, Siqian Cui, Debing Xiang, Chunrong Wu · 发表于：Frontiers in Immunology · 年份：2025 · DOI：10.3389/fimmu.2025.1677029 · 被引用次数：5 · 研究领域：Signaling Pathways in Disease、NF-κB Signaling Pathways、Peptidase Inhibition and Analysis

Background Management of the immunosuppressive tumor microenvironment (TME) is crucial for microsatellite stability (MSS) colorectal cancer (CRC), which responds poorly to immunotherapy. PIN1, a peptidyl-prolyl cis-trans isomerase that is overexpressed in human malignancies, regulates TME immunosuppression. However, its role in MSS CRC remains insufficiently explored. Methods We divided 411 CRC patients from the TCGA-COAD database into MSS or microsatellite instability-high (MSI-H) groups and analyzed their gene expression profiles. Using smoothed t-statistic SVM, weighted correlation network analysis, and sample clustering, we identified PIN1 as a key biomarker. We assessed Pin1 expression in CRC cell lines and tissues, and conducted functional assays, in vitro co-cultures, and in vivo studies (using a Pin1 inhibitor and anti-PD-1 in CT26 subcutaneous tumor and liver metastasis mouse models) to evaluate its effects and mechanisms. Results PIN1 was overexpressed in MSS CRC and negatively correlated with CD4+ T and CD8+ T cell infiltration. Knockdown of PIN1 in MSS CRC cells significantly reduced cell proliferation (assessed by CCK-8 assay), impaired migratory capacity (assessed via wound-healing assay), and increased the apoptotic rate (detected by flow cytometry). In CT26 mouse models, combining Pin1 inhibition with PD-1 blockade enhanced immunotherapy efficacy by reducing Treg infiltration, suppressing cancer-associated fibroblast (CAF) activity, and promoting CD8+ T cell r...