嵌合抗原受体（CAR）T细胞疗法显示出在治疗血液癌方面很有前途，但是抵抗力很常见，在实体肿瘤中的功效也受到限制。我们发现，CAR T细胞通过慢性刺激自主地传播了表观遗传编程的I型干扰素信号，这会妨碍抗肿瘤功能。EGR2转录调节剂敲除不仅可以阻止这种I型干扰素介导的抑制性程序，而且还可以独立地扩展早期记忆CAR T细胞，在液体和实体肿瘤的治疗方面有更好的功效。EGR2细胞因子敲除在CAR T细胞中对慢性抗原引起的筋疲力尽的保护作用可以被干扰素β暴露所覆盖，这表明EGR2的消融通过抑制I型干扰素信号可以抑制功能障碍。最后，细化的EGR2基因特征是I型干扰素相关的CAR T细胞失败和患者生存期缩短的生物标志。这些发现将持续的CAR T细胞激活与有害的免疫炎症信号联系起来，并指出EGR2-I型干扰素轴是一个可治疗的生物学系统。

Chimeric antigen receptor (CAR) T-cell therapy has shown promise in treating hematological cancers, but resistance is common, and efficacy is limited in solid tumors. We found that CAR T-cells autonomously propagate epigenetically-programmed type I interferon signaling through chronic stimulation, which hampers antitumor function. EGR2 transcriptional regulator knockout not only blocks this type I interferon-mediated inhibitory program, but also independently expands early memory CAR T-cells with improved efficacy against liquid and solid tumors. The protective effect of EGR2 deletion in CAR T-cells against chronic antigen-induced exhaustion can be overridden by interferon-β exposure, suggesting that EGR2 ablation suppresses dysfunction by inhibiting type I interferon signaling. Finally, a refined EGR2 gene signature is a biomarker for type I interferon-associated CAR T-cell failure and shorter patient survival. These findings connect prolonged CAR T-cell activation with deleterious immunoinflammatory signaling and point to an EGR2-type I interferon axis as a therapeutically amenable biologic system.