Background: The SUMO E3 ligase PIAS1 (Protein Inhibitor of Activated STAT1) regulates pathways such as TGFβ signaling and has been implicated in multiple cancers. However, its role in the tumor microenvironment (TME), particularly in non-malignant stromal and immune cells, remains poorly understood. This study aimed to characterize the expression and functional relevance of PIAS1 within the TME of oral squamous cell carcinoma (OSCC). Methods: PIAS1 protein expression was assessed via immunohistochemistry (IHC) on OSCC tissue microarrays. Single-cell RNA-sequencing (scRNA-seq) datasets from OSCC tumors and normal tissues were analyzed to map cell-type-specific PIAS1 expression. Downstream effects were evaluated using differential gene expression, Ingenuity Pathway Analysis (IPA), gene set enrichment analysis (GSEA), and cell–cell communication inference. Results: IHC analysis revealed that higher stromal PIAS1 levels correlated with improved survival. scRNA-seq analysis showed an increase in the proportion of PIAS1-expressing cells across most stromal and immune cell populations within OSCC-derived tumors compared to their counterparts in adjacent normal tissue. However, when comparing PIAS1-positive cells, expression levels were significantly reduced in cancer cells, CAFs, TAMs, T cells, and endothelial cells within the TME. PIAS1-positive CAFs, TAMs, and T cells exhibited activation of apoptotic and tumor-suppressive pathways, while PIAS1-negative counterparts showed enrichment of immunosuppressive signaling and immune checkpoint expression. Cell–cell communication analyses indicated that PIAS1 fosters an immune-activated TME by promoting pro-inflammatory signaling, M1-like TAM polarization, and T cell activation. Conclusions: PIAS1 expression in stromal and immune cells is associated with tumor-suppressive reprogramming of the OSCC microenvironment. These findings position PIAS1 as a potential modulator of anti-tumor immunity and candidate target for therapeutic intervention.
背景：SUMO E3连接酶PIAS1（活化STAT1蛋白抑制剂）可调控TGFβ信号通路等多种途径，并在多种癌症中发挥作用。然而，其在肿瘤微环境（TME）中的作用，特别是在非恶性基质细胞和免疫细胞中的功能，目前尚不清楚。本研究旨在阐明PIAS1在口腔鳞状细胞癌（OSCC）TME中的表达特征及其功能相关性。方法：通过免疫组织化学（IHC）检测OSCC组织芯片中PIAS1蛋白的表达水平。分析来自OSCC肿瘤及正常组织的单细胞RNA测序（scRNA-seq）数据集，以绘制PIAS1的细胞类型特异性表达图谱。通过差异基因表达分析、Ingenuity通路分析（IPA）、基因集富集分析（GSEA）及细胞间通讯推断评估其下游效应。结果：IHC分析显示，基质细胞中较高的PIAS1水平与患者生存期改善相关。scRNA-seq分析表明，与邻近正常组织相比，OSCC来源肿瘤中大多数基质细胞和免疫细胞群体内表达PIAS1的细胞比例有所增加。然而，在比较PIAS1阳性细胞时发现，TME内的癌细胞、癌症相关成纤维细胞（CAFs）、肿瘤相关巨噬细胞（TAMs）、T细胞及内皮细胞中PIAS1的表达水平显著降低。PIAS1阳性的CAFs、TAMs和T细胞表现出凋亡通路和肿瘤抑制通路的激活，而PIAS1阴性细胞则显示免疫抑制信号传导和免疫检查点表达的富集。细胞间通讯分析表明，PIAS1通过促进促炎信号传导、M1型TAM极化及T细胞活化，促进免疫激活型TME的形成。结论：基质细胞和免疫细胞中PIAS1的表达与OSCC微环境的肿瘤抑制性重编程相关。这些发现表明PIAS1可能作为抗肿瘤免疫的潜在调节因子及治疗干预的候选靶点。
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