Abstract / Summary
Abstract Chimeric antigen receptor (CAR) T-cell therapy has reshaped the treatment of hematologic malignancies, leading to remarkable responses in diseases that were once considered largely refractory. However, its translation to solid tumors, and particularly to glioblastoma (GBM), has remained far more limited. GBM continues to be one of the most aggressive and treatment-resistant brain tumors, characterized by profound intratumoral heterogeneity, restricted immune cell trafficking, and a highly immunosuppressive tumor microenvironment. These features collectively constrain the efficacy of CAR-T cells within the central nervous system (CNS). In this review, we propose a conceptual framework in which CAR-T-associated neurotoxicity is not interpreted solely as a treatment-induced adverse event but rather as the consequence of immune activation occurring within a preconditioned neuroinflammatory landscape. We propose that blood-brain barrier (BBB) disruption, myeloid-driven inflammation, vascular dysfunction, and intracranial spatial constraints collectively establish a vulnerable CNS state that amplifies CAR-T-induced inflammatory responses. In this regard, cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and tumor inflammation-associated neurotoxicity (TIAN) can be understood as interconnected and spatially modulated manifestations of a shared pathophysiological process. By integrating these processes, we provide a unified framework that links CNS-specific biology with immune-mediated toxicity across different clinical settings. This integrative perspective provides a mechanistic framework for interpreting neurotoxicity in GBM and may inform the development of safer and more effective CAR-T cell therapies. This highlights the importance of developing context-adapted CAR-T and combination strategies that account for the pre-existing tumor microenvironment and its associated baseline neuroinflammatory state, as key determinants of treatment-related toxicity.