FIGURE 4.

Molecular mechanism of endothelial cell dysregulation during immune effector cell‐associated neurotoxicity syndrome (ICANS) development. During ICANS after chimeric antigen receptor T‐cell (CAR‐T) treatment, excessive circulating IL‐6 along with IL‐6/sIL‐6 complex has pro‐inflammation effect on EC through Ras/MEK/MAPK pathway, PI3K/AKT pathway, and JAK/STAT3 pathway to produce more IL‐6 that establish positive feedback. TNF‐α binds to TNFR and transduces signaling through NF‐κB pathway to promote inflammation in EC. In addition, TNF increases ROS accumulation to upregulate MMP2/9‐mediated ECM degradation that contributes to endothelium disintegrity. Damage associated molecular patterns (DAMPs) may also lead to endothelium injury with exposure of tissue factor and collagen, and induce vWF release from Weibel–Palade bodies into extracellular space, which promote coagulation and thrombus.