Applications of transcranial focused ultrasound for primary brain tumors

Individuals diagnosed with primary brain tumors (PBTs) experience major morbidity and mortality, compounded by the risks associated with standard-of-care brain-directed therapeutic approaches. Recurrence remains inevitable in patients with high-grade gliomas (HGG), due to their brain-infiltrative growth hindering surgical removal, immunosuppressive tumor-microenvironment, dynamic disease evolution from their high cellular and molecular heterogeneity, and multi-faceted challenges to brain drug delivery, primarily stemming from the blood-brain barrier (BBB). This expert narrative review describes the current state of transcranial focused ultrasound (FUS), and its multi-modal applications for PBTs, including delivery of therapeutic agents and sono-liquid biopsy (via BBB opening), immunomodulation, radio-sensitization, and direct destruction of tumor cells/tissue via thermoablation, histotripsy, and sonodynamic therapy. BBB opening-based approaches have the most promising clinical evidence so far, warranting randomized comparative evalutions. Further translation will require standardized FUS treatment protocols, translational investigations nested into trials, coordinated global efforts, strategic trial design incorporating methodological advances, and implementation approaches enabling broader participation. Worldwide efforts to advance FUS will be aided by ongoing device evolution, support from professional societies, and the development of FUS research consortia (like ReFOCUSED). FUS applications open a potential combinatorial path forward with systemic therapies for "adaptive theragnostic" tumor management, thus targeting the root causes of therapeutic failure for HGG patients.