Glioblastoma: epidemiology, molecular pathogenesis, diagnosis, management, and therapeutic resistance

Abstract Glioblastoma (GBM) remains the most common and lethal primary malignant brain tumor in adults, with a median survival of approximately 15 months despite maximal multimodal therapy. The 2021 WHO classification has improved diagnostic precision by incorporating key molecular features, including EGFR amplification, TERT promoter mutation, PTEN loss, and MGMT promoter methylation. However, current standard of care treatments such as surgical resection, radiotherapy, temozolomide, and tumor treating fields have reached a therapeutic plateau, highlighting the urgent need for new therapeutic strategies. Although immunotherapy has transformed the treatment of several solid tumors, its clinical benefit in GBM remains limited. This limitation reflects not only low tumor mutational burden or blood brain barrier constraints, but also the profound spatial and temporal heterogeneity of the tumor. Distinct tumor regions exhibit diverse immune states, while ongoing clonal evolution dynamically reshapes antigenicity, immune recognition, and therapeutic response. In this review, we provide a comprehensive overview of glioblastoma, including epidemiology, molecular pathogenesis, diagnostic approaches, tumor microenvironment, intratumoral heterogeneity, and current therapeutic strategies. We further synthesize recent advances in spatial and longitudinal profiling technologies to describe the dynamic tumor immune ecosystem. We discuss how spatial compartmentalization and evolutionary processes collectively drive immune escape and therapeutic resistance, and highlight emerging strategies including adaptive immunotherapy, precision targeted delivery, and multimodal monitoring to overcome these challenges.