Advances in Treatment Approaches for IDH Wild-Type Glioblastoma

Abstract

IDH-wild-type glioblastoma (WHO CNS Grade IV; known as glioblastoma multiforme, GBM) is the most malignant and recurrent brain tumor in the central nervous system. Research on GBM primarily focuses on its mechanisms and immunotherapy. However, due to cold tumor characteristics such as the immunosuppressive tumor microenvironment (TME), blood-brain barrier (BBB) obstruction, and tumor heterogeneity, immunotherapy regimens remain in the clinical trial phase. Overcoming core challenges including BBB barrier, TME, and tumor proliferation, invasion, and migration is urgently needed. The review focuses on the molecular mechanism and comes up with target strategy. The core components in these JAK/STAT, RAGE pathway are one of most important and efficient sites which has a potential inhibiting GBM. In terms of strategy of sorting out BBB, CL5B targets claudin-5 to reversibly open BBB. Together with approaches such as the FG-PIC system, this strategy has demonstrated encouraging efficacy and provides a potential route to overcome BBB-associated drug resistance. Moreover, the combination of acriflavine and photodynamic therapy (PDT) increases CD8⁺T-cell infiltration by approximately 1.3-fold and markedly alleviates the immunosuppressive TME. These effects suggest a feasible strategy to address therapeutic resistance caused by both BBB limitation and TME-driven immune suppression. Overall, treatment strategies aimed at the “cold tumor” features of glioblastoma (GBM) offer new perspectives for GBM therapy.