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Pancreatic ductal adenocarcinoma (PDAC) is characterized by a prominent desmoplastic response created by cancer-associated fibroblasts (CAFs) that can acquire both tumor-promoting and -restraining functions. Recently, transcriptionally distinct subpopulations of CAFs have been identified in PDAC including tumor-restraining myofibroblastic CAFs (myCAFs) producing extracellular matrix and tumor-promoting inflammatory CAFs (iCAFs) secreting cytokines. While CAF heterogeneity can be driven in part by growth factor and cytokine gradients, other factors involved in shaping the CAF state in PDAC are largely unknown. Identifying and targeting such factors may help to drive CAFs from tumor-promoting into tumor-suppressive states. Hypoxia is a major environmental factor in the PDAC tumor microenvironment but its role in CAF plasticity is unknown. In this study, we use KPC organoid orthotopic transplantation and co-culture models to investigate the role of hypoxia in regulating the CAF state and functions. We find that iCAFs display a hypoxic gene expression and biochemical profile in vivo and are enriched in hypoxic regions of PDAC tumors. Hypoxia leads to acquisition of an inflammatory gene expression signature in fibroblasts and synergizes with cancer cell-derived IL1 to promote an iCAF phenotype in a HIF-1α dependent fashion. Furthermore, we show in PDAC organoid co-culture models that HIF-1α stabilization is sufficient to induce an iCAF phenotype in pancreatic stellate cells and to promote PDAC tumor growth in vivo in the absence of hypoxia. These data indicate Citation Format: Simon Schwoerer, Manon Ros, Kaloyan Tsanov, Francesco Cimino, Scott Lowe, Carlos Carmona-Fontaine, Craig Thompson. Hypoxia synergizes with IL1 to promote an inflammatory fibroblast state in the pancreatic tumor microenvironment [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr PR018.