From CAF subtypes to clinically relevant states: cancer-associated fibroblasts in pancreatic ductal adenocarcinoma

Abstract

Pancreatic ductal adenocarcinoma (PDAC) develops within a dense, poorly perfused tumor microenvironment (TME) in which cancer-associated fibroblasts (CAFs) are prominent cellular and structural components. Once viewed as a uniform population of activated matrix-producing cells, CAFs now include myofibroblastic, inflammatory, antigen-presenting and other populations identified by single-cell and spatial studies. These categories sharpen experimental resolution but do not form a stable hierarchy. CAF phenotypes overlap across spatial niches and disease stages, and they change under metabolic stress or treatment. We frame this heterogeneity as a set of context-dependent functional states. This review synthesizes evidence on fibroblast origins, canonical and recently reported states, and the signals that drive state transitions. It then examines CAF functions in extracellular matrix organization, tumor-cell plasticity and dissemination, metabolic support and immune regulation. Findings on tumor-restraining fibroblasts and protective collagen pools challenge indiscriminate stromal depletion. We also assess CAF states as prognostic and predictive biomarkers, their roles in treatment resistance and therapeutic strategies based on depletion, pathway blockade or stromal normalization. Failures of Hedgehog and hyaluronan-directed therapies show that target abundance alone cannot select patients. Clinical translation will require state definitions that integrate function, spatial context and treatment history, supported by reproducible markers, prospective validation and models that retain human stromal diversity.