Advancing Glioblastoma Treatment: The Emerging Role of CAR-T Cell Therapy

A BSTRACT Glioblastoma (GBM) remains one of the most aggressive and lethal brain tumors, with standard treatment – comprising maximal surgical resection followed by radiotherapy and temozolomide – offering only modest improvements in survival. Despite these interventions, the 5-year mortality rate exceeds 89%, highlighting the urgent need for more effective therapies. Chimeric antigen receptor (CAR) T-cell therapy has emerged as a promising immunotherapeutic approach, offering a novel strategy to redirect autologous T-cells against tumor-specific antigens. In this review, we have included an overview of GBM biology, a detailed understanding of CAR-T cell structure and function, and a comprehensive analysis of key clinical trials targeting GBM-associated antigens such as EGFRvIII, Interleukin-13 receptor alpha 2 (IL13Rα2), and HER2. We also explore novel targets, including B7-H3, CD70, and chlorotoxin, along with their translational potential. Despite early clinical promise, several challenges remain, including the brain’s immune privilege and the restrictive nature of the blood–brain barrier, which limits the delivery of therapeutic agents. Moreover, the highly immunosuppressive tumor microenvironment, characterized by pro-tumor immune cells and inhibitory cytokines, further impedes immune-based treatments. Additional obstacles such as tumor heterogeneity, hypoxic conditions, and T cell exhaustion reduce the efficacy of conventional and emerging therapies alike. In this context, CAR-T cell therapy offers a promising alternative by targeting tumor-specific antigens such as EGFRvIII, IL13Rα2, and B7-H3, potentially overcoming some of the limitations of existing treatments and providing new hope for glioblastoma patients.