Disruption of Super‐Enhancers in Activated Pancreatic Stellate Cells Facilitates Chemotherapy and Immunotherapy in Pancreatic Cancer

Abstract One major obstacle in the drug treatment of pancreatic ductal adenocarcinoma (PDAC) is its highly fibrotic tumor microenvironment, which is replete with activated pancreatic stellate cells (a‐PSCs). These a‐PSCs generate abundant extracellular matrix and secrete various cytokines to form biophysical and biochemical barriers, impeding drug access to tumor tissues. Therefore, it is imperative to develop a strategy for reversing PSC activation and thereby removing the barriers to facilitate PDAC drug treatment. Herein, by integrating chromatin immunoprecipitation (ChIP)‐seq, Assays for Transposase‐Accessible Chromatin (ATAC)‐seq, and RNA‐seq techniques, this work reveals that super‐enhancers (SEs) promote the expression of various genes involved in PSC activation. Disruption of SE‐associated transcription with JQ1 reverses the activated phenotype of a‐PSCs and decreases stromal fibrosis in both orthotopic and patient‐derived xenograft (PDX) models. More importantly, disruption of SEs by JQ1 treatments promotes vascularization, facilitates drug delivery, and alters the immune landscape in PDAC, thereby improving the efficacies of both chemotherapy (with gemcitabine) and immunotherapy (with IL‐12). In summary, this study not only elucidates the contribution of SEs of a‐PSCs in shaping the PDAC tumor microenvironment but also highlights that targeting SEs in a‐PSCs may become a gate‐opening strategy that benefits PDAC drug therapy by removing stromal barriers.