南京医科大学学报（自然科学版）2026，Vol.46Issue(1)：1-13,13.DOI:10.7655/NYDXBNSN250405
肿瘤相关成纤维细胞分泌THBS2通过PI3K/AKT通路驱动巨噬细胞M2极化促进结直肠癌进展
THBS2 secretion by cancer-associated fibroblasts drives macrophage M2 polarization via the PI3K/AKT signaling pathway to promote colorectal cancer progression
摘要
Abstract
Objective:To investigate the effect and mechanism of cancer-associated fibroblast(CAF)in promoting M2 polarization of macrophages by secreting thrombospondin-2(THBS2).Methods:The expression and clinical significance of THBS2 in colorectal adenocarcinoma were analyzed using the TCGA database.The cellular origin of THBS2 was identified through the TISCH2 single-cell database combined with multiplex immunohistochemical staining,and its association with immune infiltration was assessed using TIMER2.0.Western blot,ELISA,and primary CAF models were utilized to validate THBS2 secretion.The regulation of THBS2 on macrophage polarization,migration,and signaling pathways was evaluated by qRT-PCR,transwell assays,and PI3K/AKT pathway analysis.Results:THBS2 expression was significantly elevated in colorectal cancer tissues and closely correlated with advanced TNM stages and poor prognosisofpatients.Single-cell sequencing and experiments confirmed that THBS2 is specifically derived from CAFs and most strongly associated with M2 macrophage infiltration.Functional experiments demonstrated that CAF-conditioned medium upregulated M2 markers interleukin(IL)-10,macrophage mannose receptor(MMR),CD206,arginase-1(ARG1)and enhanced macrophage migratory capacity.Recombinant THBS2 promoted p-PI3K/p-AKT phosphorylation levelsin macrophages compared to the IL-4 group,augmenting M2 polarization.THBS2 knockdown significantly inhibited these pro-migratory and polarization effects.Conclusion:CAF-derived THBS2 may drive macrophage M2 polarization and migration by activating the PI3K/AKT signaling pathway,thereby remodeling the colorectal cancer immune microenvironment and driving malignant progression,which provides experimental evidence for immunotherapy strategies targeting the CAF-THBS2 axis in colorectal cancer.关键词
肿瘤相关成纤维细胞/THBS2/巨噬细胞极化Key words
cancer-associated fibroblast/THBS2/macrophage polarization分类
医药卫生引用本文复制引用
XU Jia,LI Mengqi,YUAN Xiaoqin..肿瘤相关成纤维细胞分泌THBS2通过PI3K/AKT通路驱动巨噬细胞M2极化促进结直肠癌进展[J].南京医科大学学报（自然科学版）,2026,46(1):1-13,13.基金项目
国家自然科学基金(81972288) （81972288）
