Role of cancer-associated fibroblast-derived exosomes in pancreatic cancer: clinical therapeutic potential and targeting challenges

Pancreatic cancer (PC)'s lethality is determined by late diagnosis and treatment resistance. The tumor microenvironment (TME), driven by cancer-associated fibroblasts (CAFs), is a crucial contributor. Within the TME, multiple cell types, including cancer cells, stromal cells, and immune cells, produce exosomes (EXOs), which are nanoscale extracellular vesicles (EVs) that mediate intercellular communication. Among these, CAF-derived EXOs (CAF-EXOs) conduct crucial interactions with cancer cells, conveying molecular cargo that promotes tumor proliferation, invasion, metastasis, metabolic reprogramming, and chemoresistance. Because CAF-EXOs provide a source of sensitive blood-based biomarkers for early detection and represent potential therapeutic targets whose disruption might overcome stromal-driven resistance, research on CAF-EXOs is crucial for addressing the fundamental shortcomings of current PC therapy. This narrative review synthesizes the critical significance of CAF-EXOs as master regulators of PC development and therapeutic resistance. We reveal how these EVs convey specialized molecular cargo, including proteins, lipids, and non-coding RNAs. By identifying CAF-EXOs as essential mediators of chemoresistance and stromal immunosuppression, we emphasize their dual potential as attractive liquid biopsy biomarkers and therapeutic targets. The study concludes with a critical examination of the translational landscape, reviewing new strategies to target exosomal biogenesis, uptake, or cargo, while also noting the enormous biological and technological challenges that must be overcome to achieve therapeutic relevance. Ultimately, altering the CAF-EXO communication axis provides a new avenue to overcome stromal-driven resistance and improve outcomes in PC.