Focused ultrasound for reshaping the immune microenvironment in glioblastoma.

Glioblastoma (GBM) remains one of the most aggressive and treatment-resistant cancers, in part due to its highly immunosuppressive tumor microenvironment and the restricted therapeutic access imposed by the blood brain barrier (BBB). Focused ultrasound (FUS) has emerged as a promising noninvasive technology capable of transiently opening the BBB, enhancing localized therapeutic delivery, and directly modulating immune responses within the brain. Beyond its established role in drug delivery, accumulating evidence demonstrates that FUS can reshape both innate and adaptive immunity through mechanical, thermal, and cavitation-mediated bioeffects, leading to cytokine release, immune-cell recruitment, antigen presentation, and immunogenic cell death. In this review, we discuss the emerging role of FUS as an immunomodulatory platform in GBM. We first summarize the immunological consequences of different FUS modalities, including thermal ablation, histotripsy, sonodynamic therapy, and microbubble-mediated BBB opening, with emphasis on their effects on the tumor microenvironment. We then review preclinical studies combining FUS with chemotherapy, immune checkpoint blockade, CAR T-cell therapy, and nanoparticle-based therapeutics, highlighting how FUS can enhance both therapeutic delivery and antitumor immune activation. Subsequently, we examine the rapidly expanding clinical landscape of FUS in GBM, including trials focused on BBB opening, sonodynamic therapy, and sonobiopsy approaches for molecular profiling and treatment monitoring. Finally, we discuss current translational challenges, including treatment standardization, device heterogeneity, imaging requirements, and the development of next-generation ultrasound-responsive agents. Collectively, this review positions FUS not only as a delivery technology, but also as a versatile strategy for reshaping the immune microenvironment in GBM and enabling future combination immunotherapies.