Adoptive Cellular Immunotherapy in Glioblastoma: Mechanistic Insights, Clinical Progress, and Future Directions of CAR-T and TIL Therapies

Abstract

Glioblastoma remains the most common and lethal primary malignant brain tumour in adults, and outcomes have changed little despite maximal surgical resection, radiotherapy and temozolomide chemotherapy. Adoptive cellular immunotherapy, principally chimeric antigen receptor T-cell (CAR-T) therapy and tumour-infiltrating lymphocyte (TIL) therapy, has emerged as a candidate strategy to overcome the profound treatment resistance of this tumour. This review synthesises mechanistic and clinical evidence on adoptive cellular therapy in glioblastoma, covering antigen selection, the immunosuppressive tumour microenvironment, delivery routes, toxicity profiles and combination strategies. CAR-T constructs directed against epidermal growth factor receptor variant III, interleukin-13 receptor alpha 2, human epidermal growth factor receptor 2, disialoganglioside GD2 and B7-H3 have progressed through early-phase trials, with locoregional intracranial or intraventricular delivery producing transient but reproducible radiographic responses. Antigen heterogeneity, an immunologically cold and metabolically hostile microenvironment, and limited T-cell persistence continue to constrain durable benefit. TIL therapy, although transformative in melanoma, remains comparatively underexplored in glioblastoma because of low native lymphocytic infiltration and difficulty in tumour-reactive lymphocyte expansion. Combination approaches pairing CAR-T with oncolytic virotherapy, checkpoint blockade or cytokine armouring show preclinical synergy and early clinical promise. Toxicities, including cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome, require structured grading and management, particularly given the confined intracranial space. This review concludes that adoptive cellular therapy for glioblastoma has moved from proof-of-concept toward early efficacy signals, but that antigen escape, microenvironmental suppression and neuroanatomical toxicity remain the principal barriers to be resolved before broader clinical adoption.