Immune effector cell-associated neurotoxicity syndrome: integrative mechanisms, predictive biomarkers, and translational pathways for prevention in CAR T-cell therapy

Immune effector cell-associated neurotoxicity syndrome (ICANS) is a common and sometimes severe complication of chimeric antigen receptor (CAR) T-cell therapy. Although our understanding has advanced considerably, ICANS remains biologically complex and clinically variable. In this review, we synthesize current evidence on how systemic immune activation, endothelial injury, disruption of the blood-brain barrier, and neuroinflammation converge to produce neurological symptoms in affected patients. We summarize emerging predictive biomarkers across plasma, cerebrospinal fluid, electroencephalography (EEG), and neuroimaging, and organize them within a temporal framework to highlight when different signals arise and how they may support earlier recognition. We also differentiate ICANS from tumor inflammation-associated neurotoxicity (TIAN), a syndrome more frequently observed in patients with central nervous system tumors, underscoring key differences in pathogenesis, presentation, and management. Finally, we discuss conceptual approaches to multimodal risk prediction and the practical challenges that currently limit clinical implementation, including assay turnaround time, generalizability across CAR constructs and disease settings, interpretability, and ethical considerations when acting on predicted risk. We propose a pragmatic roadmap that prioritizes prospective biomarker-guided studies, standardized assay platforms, and transparent modeling strategies to help move the field from observation toward safer prevention. Taken together, this integrative perspective aims to clarify the biology of ICANS, contextualize emerging biomarkers, and support more informed and safer use of CAR T-cell therapy.