Bioengineering 3D Pancreatic Cancer Models with Fibrotic Stroma for In Vitro Cancer Modeling

Pancreatic ductal adenocarcinoma (PDAC) remains highly lethal due to late diagnosis, high malignancy, and profound resistance to therapy. Traditional two-dimensional (2D) cell cultures fail to recapitulate the complex tumor microenvironment (TME), especially the fibrotic stroma, which is crucial for the progression of PDAC and drug response. In vitro three-dimensional (3D) models, which provide more physiologically relevant features such as tight cell-cell and cell-extracellular matrix (ECM) interactions, as well as 3D architecture, have been regarded as highly promising models in PDAC research. This review summarizes some representative in vitro PDAC models, including 3D spheroids, tumor-on-a-chip, bioprinted constructs, and patient-derived organoids (PDOs), particularly focused on the advances in bioengineering strategies for the integration of the key stomal components for microenvironment recapitulation and their applications. Additionally, we discuss the current challenges facing 3D models and propose potential strategies for constructing in vitro models that more accurately simulate the pathophysiology of the fibrotic stroma, aiming for their application in clinical settings.