Focused ultrasound for brain metastases.

Brain metastases (BMs) increasingly represent a significant cause of morbidity and mortality in cancer patients. The efficacy of systemic therapies for BMs, in contrast to extracranial metastases (EMs), remains limited secondary to a host of challenges. These include insufficient drug delivery due to the blood-brain barrier and blood-tumor barrier, the unique immunological milieu in the tumor microenvironment and cerebrospinal fluid, the diversity of immunogenomic landscapes in BMs across genetically distinct malignancies, the branching evolution of BM from EMs, and the challenges in longitudinally obtaining information regarding clinically actionable genetic alterations in BMs for precision oncology. These complex, long-standing challenges require treatment strategies that address multiple problems concurrently, as represented by the potential of focused ultrasound (FUS) for enhancing effectiveness of several existing BM-specific management strategies. Beyond historically investigated applications of FUS for BMs, including thermoablation and histotripsy, new frontiers include enhanced drug delivery of systemic therapies, plasma sono-liquid biopsy of BM-derived factors, radiosensitization, and immunomodulation. These applications, as discussed here, enable multiple combinatorial opportunities of FUS with targeted- and/or immunotherapies for BMs. With multiple ultrasound delivery platforms (including MR-guided, neuro-navigation-guided, and implantable devices) being investigated in neuro-oncology trials worldwide, this review provides strategies for designing and optimizing future research efforts.