Single-cell transcriptional dissection illuminates an evolution of immunosuppressive microenvironment during pancreatic ductal adenocarcinoma metastasis

作者：Xiaowei Liu, Jinen Song, Meiling Yuan, Fengli Zuo, Huihui Li, Leyi Tang, Xinmin Wang, Xueyan Wang, Qian Xiao, Li Li, Xinyu Liu, Zhankun Yang, Jian‐Lin Wu, Jing Jing, Xuelei Ma, Hubing Shi · 发表于：Signal Transduction and Targeted Therapy · 年份：2025 · DOI：10.1038/s41392-025-02265-0 · 被引用次数：14 · 研究领域：Pancreatic and Hepatic Oncology Research、Single-cell and spatial transcriptomics、Immune cells in cancer

Abstract How the host immune system loses its surveillance function during the evolution from normal cell to malignancy is still largely unknown. Here, we investigate the dynamics changes of the pancreatic ductal adenocarcinoma (PDAC) tumor microenvironment by profiling 132,115 single-cell transcriptomes derived from 51 tissues, including healthy pancreatic tissue, non-metastatic PDAC primary tumors, metastatic primary tumors, and patient-matched liver metastases. The cellular proportion, bio-functional, and interaction between each cell type are carefully characterized. Aberrant copy number variations (CNVs) indicating malignant intensity are identified at chromosomes 7 and 20 of epithelial cells during tumor development. A bio-functional transition of predominant genes from physiology to pancreatic oncogenesis and metastasis is observed. Combinatorial analysis of epithelial cells and immunocytes indicates a gradient loss of immune surveillance during the malignant transformation. By dissecting cellular interaction, we unravel an incremental tumor cell-triggered apoptosis of DCs through molecular pair ANXA1-FPR1/3. Consequently, the activation and infiltration of cytotoxic CD8 + T cells are dampened progressively. Remarkably, we unveil a novel subtype of stress-response NK cells (strNK), which are characterized by robust proliferation, diminished cytolytic capabilities, and negative immune regulation. Notably, the presence of strNK cells is associated with poor prognosis of ...