Cancer‐Associated Fibroblasts: Central Players in the Plastic Pancreatic Cancer Microenvironment and Therapeutic Targeting

ABSTRACT Pancreatic cancer is a highly fatal disease characterised by a dense stroma and an immunosuppressive microenvironment. Cancer‐associated fibroblasts (CAFs) are the predominant cell type in the tumor microenvironment (TME), displaying high heterogeneity and plasticity. Evidence indicates that CAFs can either promote or suppress tumor progression and formation of an immunosuppressive microenvironment. As CAF metabolism and biological functions have been explored, it became evident that this cell population plays an important role in pancreatic cancer TME heterogeneity. Most reports discussing pancreatic ductal adenocarcinoma plasticity have not focused on CAFs, rather recognizing fibroblasts as a homogeneous community. Thus, a comprehensive review providing an overview of pancreatic cancer TME plasticity based on CAFs would help researchers better interpret and apply previous findings for this disease. Here, we summarize the current knowledge on pancreatic cancer heterogeneity, tumor development, and immune microenvironment focusing on CAFs. We explore how CAFs can metabolically rewire themselves, differentiate into various phenotypes, support tumor development, remodel the extracellular matrix, and communicate with immune cells in the TME. Finally, we discuss current and upcoming anti‐tumor strategies targeting CAFs.