Innovating Strategies and Tailored Approaches in Neuro-Oncology

Simple Summary Diffuse gliomas, including the most aggressive subtype glioblastoma, represent the most frequent primary central nervous system tumors. Despite intense chemoradiation protocols that represent the current standard of care, these cancers inevitably recur, and median overall survival does not exceed 18 months. New therapeutic options are compellingly needed for these tumors, particularly those lacking the favorable prognostic marker IDH mutation. Nonetheless, potentially druggable alterations are increasingly identified in distinct subsets of patients harboring gliomas. Targeted treatments, along with improved immunotherapeutic schedules, gene therapy, cell therapy, and physical strategies to improve drug delivery to the nervous system, are currently under extensive investigation. They bring hope for more effective therapies in these diseases with currently often a dismal outcome. Abstract Diffuse gliomas, the most frequent and aggressive primary central nervous system neoplasms, currently lack effective curative treatments, particularly for cases lacking the favorable prognostic marker IDH mutation. Nonetheless, advances in molecular biology allowed to identify several druggable alterations in a subset of IDH wild-type gliomas, such as NTRK and FGFR-TACC fusions, and BRAF hotspot mutations. Multi-tyrosine kinase inhibitors, such as regorafenib, also showed efficacy in the setting of recurrent glioblastoma. IDH inhibitors are currently in the advanced phase of clinical evaluation for patients with IDH-mutant gliomas. Several immunotherapeutic approaches, such as tumor vaccines or checkpoint inhibitors, failed to improve patients’ outcomes. Even so, they may be still beneficial in a subset of them. New methods, such as using pulsed ultrasound to disrupt the blood–brain barrier, gene therapy, and oncolytic virotherapy, are well tolerated and may be included in the therapeutic armamentarium soon.