Unveiling purine metabolism dysregulation orchestrated immunosuppression in advanced pancreatic cancer and concentrating on the central role of NT5E

作者：Junqian Zhang, Xiaobo Zhang, Ruixin Wu, Changsheng Dong · 发表于：Frontiers in Immunology · 年份：2025 · DOI：10.3389/fimmu.2025.1569088 · 被引用次数：5 · 研究领域：Biochemical and Molecular Research、Cancer, Hypoxia, and Metabolism、Cancer Immunotherapy and Biomarkers

Background: The dismal efficacy of immunotherapy for Pancreatic cancer (PC) can be predominantly ascribed to its distinctive cold-tumor properties. The by-products of purine metabolic reprogramming are extensively engaged in tumor immune modulation, influencing the functions and recruitment of immune cells and molding an immune microenvironment that is propitious for tumor growth. Methods: We harnessed single-cell transcriptomics and spatial transcriptomics to concurrently analyze the purine metabolism (PM) features of the PC microenvironment. We quantitatively appraised the PM traits of diverse cell subsets via scoring algorithms such as AUCell and Ucell. Moreover, cell development and cell-cell interaction analysis elucidated the alterations in TME induced by PM dysregulation. Additionally, we defined the PM disorder characteristics of PC patients and utilized this to assess the immune phenotypes and prognoses of the patient population. Also, we identified the crucial intermediate genes that impact PM reprogramming and the establishment of an immunosuppressive environment within the TME of PC, and validated them through spatial sectioning and cell co-culture experiments. Results: Multi - dimensional transcriptome data elucidated the unique heterogeneity of PM in the PC microenvironment, which manifested that tumor cells and fibroblasts demonstrating higher PM scores in the TME. Cellchat analysis revealed that malignant cells with elevated PM expression were concomitantly as...