<scp>ICANS</scp> After <scp>CAR</scp> ‐T Therapy: Mechanisms and Management With a Focus on Corticosteroid‐Refractory <scp>ICANS</scp>

Chimeric antigen receptor T (CAR-T) cell therapy has transformed the treatment of relapsed or refractory haematologic malignancies, but immune effector cell-associated neurotoxicity syndrome (ICANS) remains a major and potentially life-threatening complication. Although most patients with ICANS improve after standard corticosteroid therapy, a subset shows insufficient improvement or neurological deterioration after corticosteroid initiation, a clinical scenario often described as corticosteroid-refractory or steroid-refractory ICANS. ICANS develops through a cascade initiated by CAR-T cell expansion and systemic cytokine release, followed by endothelial activation, blood-brain barrier disruption, glial-driven neuroinflammation, and neuronal injury. This process may be further amplified by on-target off-tumour effects and extracellular vesicles released from CAR-T cells. ICANS risk is influenced by CAR construct design, target antigen, and disease context. Several tools may contribute to multimodal risk assessment, including the Immune Effector Cell-Associated Encephalopathy (ICE) score, EASIX/m-EASIX, ICANS-PSS, CART-NS, cytokine profiles, neurofilament light chain, electroencephalography, and imaging, although their predictive value requires further validation. This review summarises the cytokine-mediated mechanisms, product-specific risk patterns, and early recognition strategies of ICANS after CAR-T cell therapy. It also critically appraises emerging investigational approaches for corticosteroid-refractory ICANS, including cytokine-directed interventions, endothelial-stabilising strategies, tyrosine kinase inhibition, CAR-T cell depletion, intrathecal therapy, and engineered suicide gene systems.