Liang Haiyan, Zhang Suwei
Department of Reproductive Medicine, The First Affiliated Hospital of Shantou University Medical College, Shantou, 515031, Guangdong, China.
Department of Clinical Laboratory, Shantou Central Hospital, No.114 of Waima Road, Shantou, 515041, Guangdong, China.
J Ovarian Res. 2025 May 10;18(1):99. doi: 10.1186/s13048-025-01668-5.
Ovarian cancer (OC) progression is heavily influenced by the tumor microenvironment (TME), where immune suppression plays a critical role. This study explores the role of thrombospondin-1 (THBS1) in regulating tumor-associated macrophages (TAMs), T cell exhaustion, and immune checkpoint expression, as well as its transcriptional regulation by SNF2H.
We analyzed THBS1 expression and its clinical significance using publicly available datasets (TCGA-OV, GSE14407) and tissue microarrays containing OC and adjacent normal tissues. In vitro functional studies were conducted using OC cell lines (SKOV3, A2780) and co-cultures with macrophages. Chromatin immunoprecipitation (ChIP) assays and RNA interference were employed to investigate SNF2H-mediated transcriptional regulation of THBS1. In vivo, the role of THBS1 in immune suppression was validated using mouse tumor models.
THBS1 was significantly overexpressed in OC tissues and associated with poor prognosis. High levels of THBS1 correlated with increased TAM infiltration, M2 macrophage polarization, and upregulation of immune checkpoints PD-L1 and GAL-3, which contribute to T cell exhaustion. Functional assays demonstrated that THBS1 promotes macrophage recruitment and induces M2 polarization through TGF-β1 and IL-4 signaling. Additionally, ChIP assays identified SNF2H as a transcriptional regulator of THBS1, contributing to its overexpression. In vitro targeting of THBS1 reduced TAM-mediated immune suppression and restored T cell cytotoxicity.
This study positions THBS1 as a key regulator of the OC TME, linking TAM recruitment and polarization to CD8 T cell exhaustion via immune checkpoint modulation. By identifying SNF2H as a transcriptional regulator of THBS1, we offer new insights into its epigenetic dysregulation and suggest potential therapeutic strategies to reprogram the TME and improve the effectiveness of immunotherapy.
卵巢癌（OC）的进展受到肿瘤微环境（TME）的严重影响，其中免疫抑制起着关键作用。本研究探讨血小板反应蛋白-1（THBS1）在调节肿瘤相关巨噬细胞（TAM）、T细胞耗竭和免疫检查点表达中的作用，以及其受SNF2H的转录调控。
我们使用公开可用的数据集（TCGA-OV、GSE14407）以及包含OC和相邻正常组织的组织微阵列分析THBS1表达及其临床意义。使用OC细胞系（SKOV3、A2780）并与巨噬细胞共培养进行体外功能研究。采用染色质免疫沉淀（ChIP）分析和RNA干扰来研究SNF2H介导的THBS1转录调控。在体内，使用小鼠肿瘤模型验证THBS1在免疫抑制中的作用。
THBS1在OC组织中显著过表达，并与不良预后相关。高水平的THBS1与TAM浸润增加、M2巨噬细胞极化以及免疫检查点PD-L1和GAL-3的上调相关，这些均导致T细胞耗竭。功能分析表明，THBS1通过TGF-β1和IL-4信号促进巨噬细胞募集并诱导M2极化。此外，ChIP分析确定SNF2H为THBS1的转录调节因子，导致其过表达。体外靶向THBS1可降低TAM介导的免疫抑制并恢复T细胞的细胞毒性。
本研究将THBS1定位为OC TME的关键调节因子，通过免疫检查点调节将TAM募集和极化与CD8 T细胞耗竭联系起来。通过确定SNF2H为THBS1的转录调节因子，我们对其表观遗传失调提供了新的见解，并提出了重新编程TME和提高免疫治疗有效性的潜在治疗策略。
