Beyond ICANS: Cellular and Molecular Mechanisms Linking CAR T-Cell Therapy to Long-Term Neurocognitive Outcomes

Chimeric antigen receptor (CAR) T-cell therapy can cause acute immune effector cell-associated neurotoxicity syndrome (ICANS), but its delayed neurological and long-term cognitive effects remain incompletely understood. Existing reviews primarily address clinical syndromes or cognitive assessment. This narrative review provides a cross-timescale synthesis of preclinical, neuropathological, biomarker, imaging, and longitudinal clinical evidence linking systemic immune activation, neurovascular interfaces, and central nervous system (CNS) cellular responses. Human studies associate acute ICANS with endothelial and barrier dysfunction, compartmentalized inflammation, and selected astroglial or neuroaxonal injury markers. Persistent microglial reactivity, oligodendroglial alterations, and impaired neurogenesis have predominantly been demonstrated in mice; related human transcriptomic observations derive from CNS-tumor tissue and do not establish persistent injury in hematological CAR T-cell recipients. Prospective clinical cohorts show heterogeneous, often recovering cognitive trajectories rather than uniform long-term deterioration. Acute ICANS, delayed non-ICANSs, and longer-term cognitive outcomes are clinically distinguishable, although their biological separation remains incompletely established. Available treatment studies address predominantly acute toxicity and do not demonstrate prevention of persistent cognitive impairment. We propose testable neurovascular-to-glial and neuronal pathways and a baseline-anchored, multimodal longitudinal framework to connect biological responses and recovery with domain-specific cognitive outcomes.