Abstract 2074: Adenosine-driven inflammatory reprogramming of aged cancer-associated fibroblasts promotes immune suppression in pancreatic ductal adenocarcinoma.

作者：Shuncang Zhu, Jinpeng Lu, Ziyi Tu, Hongyi Lin, Yinhao Chen, Yiting Chen, Haoxiang Zhang, Zuwei Wang, Shi Chen · 发表于：Cancer Research · 年份：2026 · DOI：10.1158/1538-7445.am2026-2074 · 研究领域：Cancer Research and Treatments、Immune cells in cancer、Extracellular vesicles in disease

Abstract Background: Aging exerts a profound influence on the tumor immune microenvironment of pancreatic ductal adenocarcinoma (PDAC). In elderly patients, PDAC is frequently characterized by pronounced stromal desmoplasia, enhanced immune evasion, and increased resistance to chemotherapy. The molecular underpinnings of these age-associated alterations remain largely undefined. Emerging evidence indicates that aging-related metabolic reprogramming can profoundly reshape the cellular and immunologic composition of the tumor microenvironment (TME). Yet, the mechanistic interplay between metabolic perturbations, stromal cell dynamics, and immune regulation in aged PDAC has not been fully elucidated. Methods: Two PDAC clinical cohorts stratified by age and survival were analyzed using bulk and single-cell transcriptomics, and metabolomics. Nucleotide metabolism was assessed by targeted metabolomics. Functional studies included adenosine stimulation of aged and young cancer-associated fibroblasts (CAFs), B cell migration and co-culture assays, cytokine profiling, and orthotopic PDAC mouse models with adenosine receptor blockade. Multiplex immunohistochemistry (mIHC) was applied to spatially validate the proximity of A2B+CXCL13+ CAFs and IL-10+ Bregs in aged human PDAC tissues. Results: Aged PDAC exhibited increased regulatory B (Breg) cell abundance, which correlated with shorter overall survival. Multi-omic analyses identified age-related adenosine accumulation as the most dysre...