Focused Ultrasound in Pancreatic Ductal Adenocarcinoma: Mechanisms, Preclinical Evidence, and Emerging Clinical Applications.

Pancreatic ductal adenocarcinoma (PDAC) remains a highly lethal malignancy due to late presentation, limited resectability, therapeutic resistance, and a dense desmoplastic immunosuppressive tumor microenvironment that impairs drug penetration and antitumor immunity. Focused ultrasound (FUS) is an emerging non-invasive, image-guided therapeutic platform capable of delivering spatially confined acoustic energy to induce tumor ablation, disrupt stromal barriers, and enhance delivery of drugs, nanoparticles, and nucleic acids. Depending on acoustic parameters, FUS can produce thermal effects resulting in coagulative necrosis or non-thermal mechanical effects, including cavitation, sonoporation, and histotripsy which remodel extracellular matrix architecture, increase vascular and cellular permeability, and facilitate tumor debulking. In addition, FUS-induced cell injury can promote immunogenic cell death and release tumor-associated antigens and danger signals, providing a rationale for combination strategies with chemotherapy, radiation, and immunotherapy. This review synthesizes the mechanistic foundations, preclinical modeling advances, and emerging clinical applications of FUS in PDAC, with emphasis on treatment integration, patient selection, real-time monitoring, and acoustic parameter optimization, while acknowledging current safety considerations and limited clinical toxicity data. Key limitations, translational challenges, and priority knowledge gaps are also discussed to define the role of FUS in multimodal PDAC care.