The Potential and Challenges of Focused Ultrasound-Mediated Therapies in the Management of Liver and Biliary Tract Cancers

Focused ultrasound (FUS)-mediated therapies have evolved with the advent of modern ultrasound-guided technology and MRI imaging, moving from their initial use as thermal ablation to a multifunctional platform for thermal and non-thermal ablation, immunomodulation, and targeted drug delivery. This narrative review explores the potential, limitations, and challenges of ablative high-intensity focused ultrasound (HIFU) therapies: HIFU thermal ablation and non-thermal ablation, histotripsy, as well as non-ablative low-intensity focused ultrasound (LIFU) applications in the management of hepatobiliary cancers. HIFU and histotripsy are reviewed as alternative or complementary treatment options in liver tumors, as well as their potential as bridging therapy. Histotripsy is addressed as a theranostic tool, not only by combining ablation with real-time ultrasound imaging guidance, but also by integrating it with sonobiopsy. It facilitates a liquid sonobiopsy of the ablated tumor by releasing intact tumor antigens and damage-associated molecular patterns, leading to potential molecular profiling. LIFU-induced targeted drug delivery (sono-chemotherapy), sonodynamic therapy, radiosensitization, immunomodulation of the immunosuppressive tumor microenvironment (sono-immunotherapy), and the potential to enhance the effect of immune checkpoint inhibitors in these malignancies are discussed. Since FUS-assisted procedures exhibit dual actions through therapeutic functionality associated with intra- and post-procedural ultrasound imaging guidance, they could have value as a theranostic tool in hepatobiliary interventional oncology. Although promising, the available clinical evidence for FUS-mediated therapies in hepatobiliary malignancies consists predominantly of early-stage feasibility studies, retrospective observational cohorts, and non-randomized comparative analyses. Further studies focused on standardized protocols, validation through large-scale, multicenter, prospective randomized clinical trials comparing FUS-based therapies with established treatments, and long-term follow-up of oncological efficacy could define their future role in multimodal oncological strategies.