IL-1-activated cancer-associated fibroblasts promote STAT1-driven transcriptional reprogramming of pancreatic tumour cells

Pelicano, C.; Chernukhin, I.; Woelke, M.; Cheng, P. S. W.; Young, L.; Edwards, A. R.; Mannion, E.; Cheng, Y.; Kupczak, S.; Cronshaw, M.; Teles, S. P.; Jihad, M.; Kishore, K.; Chilamakuri, C. S. R.; Franklin, V. N. R.; Papachristou, E. K.; D'Santos, C.; Gruenwald, B.; Russell, A.; Carroll, J. S.; Biffi, G.; Rao, S. V.

doi:10.64898/2026.05.26.726819

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bioRxiv · 10.64898/2026.05.26.726819

IL-1-activated cancer-associated fibroblasts promote STAT1-driven transcriptional reprogramming of pancreatic tumour cells

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Abstract

Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest cancers, with limited treatment options and poor survival rates. It is characterised by strong driver mutations, epigenetic reprogramming, and a dense tumour microenvironment (TME). A defining feature of the PDAC TME is its fibrotic stroma, which is largely composed of cancer-associated fibroblasts (CAFs). Distinct CAF populations have been implicated in PDAC progression, but the mechanisms that govern their crosstalk with the cancer cells are poorly understood. We generated genetically engineered pancreatic stellate cells (PSCs) modelling interleukin-1 (IL-1)-dependent inflammatory CAFs (iCAFs) and transforming growth factor-{beta} (TGF-{beta})-dependent myofibroblastic CAFs (myCAFs) to investigate how distinct stromal populations shape the epigenetic landscape of pancreatic ductal adenocarcinoma (PDAC). We found that iCAFs, but not myCAFs, promoted gemcitabine resistance in epithelial tumour cells and identified STAT1 as a critical mediator of iCAF-tumour cell crosstalk. Mechanistically, STAT1 drove the induction of interferon (IFN)-responsive genes, while blockade of IFN-{beta} attenuated iCAF-mediated transcriptional reprogramming. Genetic ablation of STAT1 in tumour cells abolished iCAF-induced chemoresistance and associated transcriptional changes. In an orthotopic in vivo model, STAT1 knockout significantly prolonged survival following gemcitabine treatment, supporting a central role for STAT1 signalling in stromal-driven therapy resistance. We provide a comprehensive analysis on how IL-1-dependent iCAFs contribute to epigenetic reprogramming in PDAC and uncover a previously undescribed role for STAT1 in stromal-epithelial interactions. These findings reveal distinct, non-overlapping mechanisms by which CAF subtypes modulate tumour behaviour and identify STAT1 as a therapeutic vulnerability that can be exploited to sensitise PDAC to standard chemotherapy. Significance statementThis study establishes that the epigenetic landscape of PDAC is differentially shaped by iCAF- and myCAF-like PSCs and defines STAT1 as a mediator of iCAF-induced chemoresistance and transcriptional reprogramming. We demonstrate that genetic ablation of STAT1 sensitises tumours to gemcitabine in vivo, extending survival and positioning STAT1 as an actionable target to overcome stromal-mediated therapy resistance in PDAC.

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Pelicano, C., Chernukhin, I., Woelke, M., Cheng, P. S. W., Young, L., Edwards, A. R., Mannion, E., Cheng, Y., Kupczak, S., Cronshaw, M., Teles, S. P., Jihad, M., Kishore, K., Chilamakuri, C. S. R., Franklin, V. N. R., Papachristou, E. K., D'Santos, C., Gruenwald, B., Russell, A., Carroll, J. S., Biffi, G., Rao, S. V.. 2026-05-29. IL-1-activated cancer-associated fibroblasts promote STAT1-driven transcriptional reprogramming of pancreatic tumour cells. https://doi.org/10.64898/2026.05.26.726819

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