Cytokine release syndrome (CRS) is a severe immune-mediated toxicity frequently associated with immunotherapies such as CAR-T cells and bispecific T-cell engagers. Predicting CRS in humans remains difficult because current animal models and in vitro systems do not adequately capture the complex, systemic, and patient-specific nature of pathological inflammation. This perspective highlights key mechanistic and methodological limitations in current immunotoxicology approaches and proposes an immun