Page 7 - 《南京医科大学学报》2026年第1期

第46卷第1期 南京医科大学学报（自然科学版）
2026年1月 Journal of Nanjing Medical University（Natural Sciences） · 1 ·

·专题研究：肿瘤·

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

徐 甲，厉梦琪，袁小琴 *

南京医科大学基础医学院人体解剖学系，江苏 南京 211166

［摘 要］ 目的：探究肿瘤相关成纤维细胞（cancer⁃associated fibroblast，CAF）通过分泌血小板反应蛋白⁃2（thrombospondin⁃2，
THBS2）促进巨噬细胞M2极化的作用及机制。方法：基于癌症基因组图谱（The Cancer Genome Atlas，TCGA）数据库分析结肠
腺癌中THBS2的表达特征和临床意义；通过TISCH2单细胞数据库及多重免疫组化染色定位THBS2细胞来源，结合TIMER2.0
评估其与免疫浸润相关性；利用 Western blot、ELISA 及原代 CAF 模型验证 THBS2 分泌特征；通过 qRT⁃PCR、Transwell 及 PI3K/
AKT通路检测评估THBS2对巨噬细胞极化、迁移及信号通路的调控。结果：THBS2在结肠癌肿瘤组织中高表达，与晚期TNM
分期及患者不良预后密切相关。单细胞测序及实验证明THBS2特异性来源于CAF，与M2型巨噬细胞浸润呈强正相关。功能
实验显示，CAF 条件培养基显著上调巨噬细胞 M2 标志物［白细胞介素（interleukin，IL）⁃10、巨噬细胞甘露糖受体（macrophage
mannose receptor，MMR）、CD206、精氨酸酶1（arginase⁃1，ARG1），并促进迁移；重组蛋白THBS2激活PI3K/AKT 通路，促进巨噬
细胞M2极化，而THBS2敲低后极化及迁移效应被逆转。结论：CAF来源的THBS2可能通过激活PI3K/AKT信号通路诱导巨噬
细胞向M2极化及迁移，从而促进结直肠癌免疫微环境重塑，为靶向结直肠癌CAF⁃THBS2轴的免疫治疗提供了实验依据。
［关键词］ 肿瘤相关成纤维细胞；THBS2；巨噬细胞极化
［中图分类号］ R735.34 ［文献标志码］ A ［文章编号］ 1007⁃4368（2026）01⁃1⁃13
doi：10.7655/NYDXBNSN250405

THBS2 secretion by cancer⁃associated fibroblasts drives macrophage M2 polarization via
the PI3K/AKT signaling pathway to promote colorectal cancer progression

XU Jia，LI Mengqi，YUAN Xiaoqin *
Department of Human Anatomy，School of Basic Medicine，Nanjing Medical University，Nanjing 211166，China

［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.
［基金项目］ 国家自然科学基金（81972288）
通信作者（Corresponding author），E⁃mail：yuanxq@njmu.edu.cn（ORCID：0000⁃0002⁃3084⁃5624）
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