Hypoxia-Induced Fibroblast IL-6 Promotes Immunosuppressive Macrophage Phenotypes in Pancreatic Cancer

Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy characterized by a dense fibroinflammatory stroma and profound hypoxia. Using pancreatic stellate cell-tumor organoid coculture models and single-cell RNA sequencing analyses, we uncover that hypoxia-driven fibroblast reprogramming promotes immunosuppressive macrophage phenotypes in PDAC. Mechanistically, hypoxia acts through tumor-fibroblast crosstalk to increase IL-6 expression in fibroblasts; in turn, fibroblast-derived IL-6 induces expression of arginase 1 (ARG1), a key mediator of immunosuppression, in macrophages via activation of the JAK/STAT signaling pathway. Consistent with these findings, macrophages enriched for hypoxia signatures are strongly associated with elevated immunosuppression programs and IL6/JAK/STAT3 signaling signatures in PDAC. Our study reveals a paracrine mechanism by which hypoxia coordinates tumor cell, fibroblast, and macrophage interactions to promote immune suppression in PDAC.