Synergy of radiotherapy, focused ultrasound, and immunotherapy in the treatment of brain metastases

Abstract

PurposeBrain metastases (BrM) represent the most common intracranial malignancies and remain a major clinical challenge. Unlike glioblastoma (GBM), where immunotherapy has shown limited benefit, there are promising results for BrM. Nonetheless, several key aspects remain to be solved to amplify the success of these therapies, highlighting the potential of integrating immunotherapy with local strategies. This review focuses on therapeutic approaches for BrM, emphasizing the role of radiotherapy (RT) and focused ultrasound (FUS) in enhancing immunotherapy efficacy.MethodsWe performed a narrative review of recent clinical studies addressing the interactions between the immune system, RT, and blood–brain barrier (BBB) modulation by FUS, with an emphasis on therapeutic strategies tested in BrM.ResultsThe success of immunotherapy in brain malignancies is hindered by the immunosuppressive tumor microenvironment (TME) and limited BBB penetration, as these treatments are administered systemically. RT synergizes with immunotherapy by promoting tumor antigen release and immune priming, which helps transiently overcome the immunosuppressive TME. However, excessive and prolonged antigen exposure may lead to T-cell exhaustion and checkpoint upregulation, which explains why sequential administration of stereotactic radiosurgery (SRS) followed by immunotherapy within a 2–4-week window enhances antitumor responses. Regarding the general difficulty for systemic drugs to access the brain, FUS emerges as a potent candidate for enabling transient BBB disruption, facilitating drug delivery, and biomarker access.ConclusionCombining immunotherapy with SRS or FUS-mediated BBB modulation offers a promising path for improving outcomes in BrM. Future work must optimize these multimodal strategies while minimizing toxicity.