Abstract
On-target off-tumor effects precipitate severe adverse reactions in patients, significantly hindering the application of chimeric antigen receptor (CAR) T cells in both hematological and solid tumors. The underlying mechanisms remain elusive due to the absence of suitable preclinical models. To elucidate these mechanisms, a human epidermal growth factor receptor 2 (Her2) transgenic mouse model was developed to investigate CAR-T cell-induced on-target off-tumor effects. CAR-T cells initially migrated to the lungs, targeting alveolar epithelial cells and resulting in interferon-γ (IFN-γ)-dependent acute lung injury. Additionally, a regulatory mechanism involving IFN-γ-induced degradation of caspase-7 mRNA 5' untranslated regions (UTR), which amplifies acute lung injury mediated by CAR-T cells, was identified. Consequently, a strategy was validated to antagonize IFN-γ during CAR-T cell infusion, thereby mitigating acute lung injury without compromising antitumor efficacy. These findings elucidate the mechanisms of CAR-T cell-induced acute lung injury and demonstrate the viability of targeting IFN-γ to prevent this adverse reaction.