Focused ultrasound as a therapeutic adjunct in pancreatic cancer: from thermal and mechanical effects to immune modulation

Pancreatic cancer remains highly lethal, with only limited improvements achieved with surgery, chemotherapy, radiotherapy, or immunotherapy. Focused ultrasound (FUS) offers complementary, noninvasive therapeutic modalities-including thermal ablation, non-ablative mechanical stimulation, and histotripsy-that can debulk tumors, palliate pain, enhance drug delivery through modulation of the dense stromal environment, and stimulate antitumor immunity. Extracorporeal high-intensity focused ultrasound is clinically feasible, while endoscopic and intraoperative approaches aim to overcome anatomical constraints. Preclinical studies demonstrate cavitation-mediated increases in tissue permeability and immune activation, and early clinical trials combining FUS with chemotherapy have reported encouraging signals in response rates and survival outcomes. Ongoing investigations are evaluating synergistic effects with immunotherapies and targeted drug delivery strategies. Key challenges-including the deep anatomical location of the pancreas, its fibrotic microenvironment, and the low immunogenicity of pancreatic tumors-necessitate the standardization of treatment parameters and improvements in image guidance. Overall, FUS represents a promising adjunct within multidisciplinary pancreatic cancer care.