2. Academic Validation
  3. Single-cell transcriptional dissection illuminates an evolution of immunosuppressive microenvironment during pancreatic ductal adenocarcinoma metastasis

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

  • Signal Transduct Target Ther. 2025 Jun 9;10(1):182. doi: 10.1038/s41392-025-02265-0.
Xiaowei Liu # 1 2,  Jinen Song # 1,  Meiling Yuan 1,  Fengli Zuo 1,  Huihui Li 1,  Leyi Tang 1,  Xinmin Wang 1,  Xueyan Wang 1,  Qian Xiao 1,  Li Li 3,  Xinyu Liu 1,  Zhankun Yang 4,  Jianlin Wu 5,  Jing Jing 6,  Xuelei Ma 7,  Hubing Shi 8
Affiliations

Affiliations

  • 1 Institute for Breast Health Medicine, State Key Laboratory of Biotherapy, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
  • 2 Department of Biotherapy, West China Hospital and State Key Laboratory of Biotherapy, Sichuan University, Chengdu, Sichuan, China.
  • 3 Institute of Clinical Pathology, West China Hospital of Sichuan University, Chengdu, China.
  • 4 College of Chemical Engineering, Shijiazhuang University, Shijiazhuang, Hebei, China.
  • 5 State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China.
  • 6 Institute for Breast Health Medicine, State Key Laboratory of Biotherapy, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, Sichuan, China. jingjing@wchscu.edu.cn.
  • 7 Department of Biotherapy, West China Hospital and State Key Laboratory of Biotherapy, Sichuan University, Chengdu, Sichuan, China. drmaxuelei@gmail.com.
  • 8 Institute for Breast Health Medicine, State Key Laboratory of Biotherapy, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, Sichuan, China. shihb@scu.edu.cn.
  • # Contributed equally.
PMID: 40484878 DOI: 10.1038/s41392-025-02265-0
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 PDAC patients, implying a potential pro-tumor function. Taken together, our results not only shed light on the intricate mechanisms underlying step-wise evasion of immune surveillance during PDAC tumor development, but also provide a potential strategy for holding back malignant transition by reinforcing DCs' function.

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