Immunotherapy for Newly Diagnosed Glioblastoma: Current Evidence and Future Perspectives

Background: Glioblastoma (GBM) represents the most aggressive and lethal primary malignancy of the central nervous system in adults. Although clinical trials evaluating immunotherapy strategies have increased substantially in recent years, the available evidence remains highly fragmented. This scoping review aimed to synthesize the available evidence from clinical trials investigating immunotherapy for newly diagnosed GBM. Methods: PubMed, Scopus, Embase, and Web of Science were searched from inception to July 2026 for clinical trials of first-line immunotherapy in adults with newly diagnosed GBM; recurrent, mixed-setting, preclinical, and abstract-only reports were excluded. Outcomes were overall survival (OS) and progression-free survival (PFS), adverse events, and treatment-related deaths. Results: Six therapeutic classes were represented: immune checkpoint inhibitors (13 reports), peptide and neoantigen vaccines (12), dendritic cell vaccines (10), adoptive cell therapies (5), oncolytic viral and gene therapies (3), and autologous formalin-fixed tumor vaccines (2). The evidence base was predominantly early-phase: 36 of 45 studies enrolled fewer than 100 patients, only 14 included a randomized comparison, and 5 were phase III. Median OS ranged from 11.5 to 38.4 months and median PFS from 1.3 to 60.1 months, the highest estimates arising from small, highly selected single-arm cohorts. No randomized trial improved OS. Important adverse events were rare and almost exclusively confined to checkpoint inhibitor trials. Conclusions: Immunotherapy in newly diagnosed GBM is feasible and tolerable but has not improved survival, with outcomes still determined more by MGMT promoter status and extent of resection than by treatment assignment. Biomarker-enriched selection, lymphocyte-sparing design and rational combinations are required in future trials.