Cancer-associated fibroblasts (CAFs) are a major stromal component across solid tumors, but their biological and therapeutic relevance is particularly pronounced in pancreatic ductal adenocarcinoma (PDAC), where dense desmoplasia, immune exclusion, and treatment refractoriness converge. Emerging single-cell, spatial, and multi-omics studies indicate that CAF heterogeneity is more appropriately understood as the context-dependent deployment of conserved stromal programs across cancers, rather than as an ever-expanding list of subtype labels. In PDAC, these programs are classically represented by myofibroblastic, inflammatory, and antigen-presenting CAF states, with additional transitional and lineage-biased populations becoming apparent as profiling resolution improves. Functionally, CAF programs converge on four interrelated axes—mechanical remodeling, immune instruction, metabolic regulation, and therapeutic adaptation—through which they shape extracellular matrix architecture, immune topology, nutrient availability, and treatment response. These activities confer the paradoxical, double-edged nature of CAFs: certain stromal programs reinforce immune evasion, drug resistance, and metastatic progression, whereas others constrain tumor expansion, preserve tissue architecture, or support anti-tumor immunity in specific contexts. This framework helps explain why indiscriminate stromal depletion has produced disappointing or even deleterious outcomes in preclinical and clinical settings. In this review, we synthesize CAF programs across cancers and map them onto the specific biology of PDAC, with emphasis on lineage contribution, spatial organization, functional plasticity, and translational vulnerabilities. We further discuss emerging therapeutic strategies centered on subtype-aware modulation and stromal reprogramming, aiming to advance a more precise and biologically grounded approach to CAF-targeted therapy in PDAC.
Xu et al. (Mon,) studied this question.