PROJECT SUMMARY: Pancreatic cancer accounts for approximately 3% of all cancers in the United States and approximately 7% of all cancer related deaths. New treatment paradigms are direly needed. Emerging tumor ablation techniques have shown significant promise in both clinical and pre-clinical cancer studies. This proposal will focus on histotripsy, which is the first non-invasive, non-ionizing, non-thermal, image-guided tumor ablation modality that destroys tumors through the precise control of acoustic cavitation and is capable of overcoming many of the limitations of the other tumor ablation modalities currently under development for this malignancy. Recently, our research team completed proof-of-concept studies demonstrating that histotripsy is effective at targeting the pancreas and produces consistent, fast, and complete ablations, even in proximity to critical structures. Intriguingly, work by our team and others has also shown that histotripsy is effective in inducing systemic anti-tumor responses, resulting in post-treatment tumor regression both locally and at metastatic sites. However, the exact mechanism and level of control of this phenomenon is still unclear. The objective of this proposal is to utilize our pre-clinical mouse and novel pig animal models to expand upon the preliminary data presented in this proposal to generate critical mechanistic, safety, and efficacy data necessary to support future clinical trials in pancreatic cancer patients. Our overarching hypothesis is that histotripsy can achieve safe and selective focal ablation of pancreatic tumors and improve systemic anti-tumor immune responses. SPECIFIC AIM 1: Determine histotripsy treatment parameters for precise and complete pancreatic tumor ablation. Our preliminary data demonstrates the general feasibility of histotripsy ablation in the pancreas. This Aim will test the hypothesis that histotripsy can achieve precise, efficient, and complete ablation of pancreatic tumors without injuri