整合多组学分析揭示EBV相关的MIF-SPP1+巨噬细胞轴连接鼻咽癌中的肿瘤干性与免疫功能障碍
Integrated Multiomic Analysis Reveals an EBV-Associated MIF-SPP1+ Macrophage Axis Linking Tumor Stemness and Immune Dysfunction in Nasopharyngeal Carcinoma.
文献信息
| PMID | 42966886 |
|---|---|
| 原文 | 在 PubMed 查看原文 ↗ |
| 发表日期 | 2026 |
| 作者 | Guo-Ying Liu |
| 作者单位 | Department of Nasopharyngeal Carcinoma, Sun Yat-sen University Cancer Center, the State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou, China. |
| 期刊 | Advanced science (Weinheim, Baden-Wurttemberg, Germany) |
| SCI 分区 | Q1 |
| IF | 15.6 |
| 研究类型 | 基础研究 · 基础／转化 |
| 所属专科 | 鼻咽癌 |
中文摘要
阐明Epstein-Barr病毒（EBV）如何塑造肿瘤-免疫相互作用对于改善鼻咽癌（NPC）的治疗具有重要意义。本多队列分析整合了单细胞、空间和批量转录组数据，并结合多重免疫荧光和功能实验。单细胞分析识别出干性相关上皮状态以及EBV+ NPC中SPP1+肿瘤相关巨噬细胞（TAM）的富集。SPP1+ TAM丰度与干性相关上皮特征和功能障碍T细胞状态相关，而高MIF和SPP1+巨噬细胞特征与较短的无进展生存期相关。在EBV+空间队列中，SPP1+ TAM与干性相关肿瘤细胞、耗竭CD8+ T细胞和调节性T细胞在Niche 5中共存，该生态位在化疗免疫治疗后无应答肿瘤中更常见。功能实验显示EBV+上皮细胞中MIF表达和分泌增加。MIF抑制减弱条件培养基诱导的单核细胞迁移和SPP1相关TAM样编程，而重组MIF可重现这些效应。相反，巨噬细胞来源的SPP1增加EBV+上皮和肿瘤模型中干性相关标志物表达和肿瘤球形成。它还损害原代CD8+ T细胞增殖、效应功能和细胞毒活性，同时增加耗竭相关标志物；CD44阻断可部分逆转这些效应。总体而言，这些发现支持一种EBV相关的MIF-SPP1巨噬细胞-肿瘤/T细胞串扰模型，将干性相关上皮表型与免疫功能障碍和不良临床结局联系起来。
英文摘要
Elucidating how Epstein-Barr virus (EBV) shapes tumor-immune interactions is important for improving therapy in nasopharyngeal carcinoma (NPC). This multi-cohort analysis integrates single-cell, spatial, and bulk transcriptomic data with multiplex immunofluorescence and functional assays. Single-cell profiling identifies stemness-associated epithelial states and enrichment of SPP1+ tumor-associated macrophages (TAMs) in EBV+ NPC. SPP1+ TAM abundance is associated with stemness-associated epithelial features and dysfunctional T-cell states, while high MIF and SPP1+ macrophage signatures are associated with shorter progression-free survival. Within the EBV+ spatial cohort, SPP1+ TAMs co-occur with stemness-associated tumor cells, exhausted CD8+ T cells, and regulatory T cells in Niche 5, which is more frequent in non-response tumors following chemoimmunotherapy. Functional experiments show increased MIF expression and secretion by EBV+ epithelial cells. MIF inhibition attenuates conditioned-medium-induced monocyte migration and SPP1-associated TAM-like programming, whereas recombinant MIF reproduces these effects. Conversely, macrophage-derived SPP1 increases stemness-associated marker expression and tumorsphere formation in EBV+ epithelial and tumor models. It also impairs primary CD8+ T-cell proliferation, effector function, and cytotoxic activity while increasing exhaustion-associated markers; CD44 blockade partially reverses these effects. Collectively, these findings support an EBV-associated MIF-SPP1 macrophage-tumor/T-cell crosstalk model linking stemness-associated epithelial phenotypes with immune dysfunction and adverse clinical outcomes.