Immunobiology and Immune-Related Toxicities of Cancer Immunotherapy: Organ-Specific Immune-Related Adverse Events, Cytokine Release Syndrome, and Immune Effector Cell–Associated Neurotoxicity Syndrome

Immune checkpoint inhibitors (ICIs) and immune effector cell (IEC) therapies have transformed cancer treatment but cause distinct immune-mediated toxicities. This review synthesizes current evidence and consensus guidance on the immunobiology, clinical manifestations, and management of these complications. ICIs targeting CTLA-4, PD-1, PD-L1, and LAG-3 can disrupt immune tolerance, producing autoimmune-like immune-related adverse events (irAEs) affecting multiple organs, including the skin, gastrointestinal tract, endocrine system, lungs, liver, nervous system, heart, kidneys, and hematologic system. Management requires early recognition, exclusion of alternative diagnoses, and severity-based immunosuppression, typically corticosteroids with targeted agents for refractory disease such as infliximab, vedolizumab, mycophenolate mofetil, or abatacept. In contrast, IEC therapies, including CAR T-cell therapies and CD3-engaging bispecific antibodies, instead cause hyperinflammatory toxicities driven by rapid T-cell activation and cytokine amplification. Cytokine release syndrome (CRS) and immune effector cell–associated neurotoxicity syndrome (ICANS) are the principal acute complications and are managed with close monitoring, organ support, IL-6 blockade with tocilizumab, and corticosteroids. Other complications include HLH-like hyperinflammatory syndromes, prolonged cytopenias, and infectious complications associated with immune dysfunction. As immunotherapies expand into earlier treatment settings and broader patient populations, effective toxicity management has become central to safe and successful cancer immunotherapy. Distinguishing autoimmune irAEs from hyperinflammatory IEC-associated syndromes provides a mechanistic framework for diagnosis and treatment. Continued integration of translational insights, standardized toxicity frameworks, and multidisciplinary clinical care will be essential to optimize patient outcomes while preserving the benefits of modern cancer immunotherapy.