REVIEW article
Front. Neurol.
Sec. Experimental Therapeutics
This article is part of the Research TopicNovel Insights into CAR T-cell Associated Neurotoxicity - Volume IIView all 4 articles
Immune Effector Cell–Associated Neurotoxicity Syndrome (ICANS): Integrative Mechanisms, Predictive Biomarkers, and Translational Pathways for Prevention in CAR T-Cell Therapy
Provisionally accepted
- 1CellGene Nexus, Rosharon, TX, United States
- 2University of Minnesota Twin Cities The Hormel Institute, Austin, United States
- 3University of Texas MD Anderson Cancer Center, Houston, United States
- 4The University of Texas at El Paso, El Paso, United States
Select one of your emails
You have multiple emails registered with Frontiers:
Notify me on publication
Please enter your email address:
If you already have an account, please login
You don't have a Frontiers account ? You can register here
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.
Keywords: Biomarker framework, CAR T-cell therapy, endothelial dysfunction, immune effector cell-associated neurotoxicity (ICANS), Neuroinflammation, Translational neurotherapeutics
Received: 04 Nov 2025; Accepted: 06 Feb 2026.
Copyright: © 2026 Aziz, Chakraborty, Saha and Dutta. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Faisal Aziz
Abhijit Chakraborty
Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.