Abstract An adverse effect of Chimeric Antigen Receptor (CAR) T-cell therapy is endothelial activation leading to systemic and neurologic toxicities. Regulating this unwanted byproduct can facilitate the design of safe and efficacious immunotherapies. Yet, the signaling pathways manifesting endothelial cell activation are poorly defined, preventing critical improvements to the therapeutic safety profile. Here we identify a potential mechanism by which CAR T-cell therapy precipitates endothelial activation through alternative IFNγ signaling. IFNγ is classically mediated by STAT1 programming, yet our results identify increased STAT3 activity, not STAT1, as being associated with the characteristic response to CAR T-cell activity. Blockade of STAT3 by RNA interference (RNAi) demonstrate that reducing endothelial-STAT3 can attenuate the effect of CAR T-cells on endothelial cell activation. The findings reported here suggest targeting endothelial-STAT3 as a potential strategy for mitigating endothelial cell activation and reducing CAR T-cell toxicities.
Rosén et al. (2026) studied this question.