CAR T cell therapies are limited by exhaustion of these cells in vivo, especially in treating solid tumors. Positive treatment responses have been associated with improved T cell fitness, but it is not known which transcription factors drive these fitness programs. Two papers published in Nature have now identified FOXO1 as a strong enhancer of CAR T cell function that boosts antitumor activity, memory and metabolic fitness. Overexpressing FOXO1 enhances in vivo T cell potency and makes the cells more effective against various cancers, including solid tumors.

Although the two teams used different approaches to search for transcription factors that improve treatment outcome, both identified FOXO1 as a master regulator. Doan and colleagues show that FOXO1 inhibition impairs expression of memory genes, with cells attaining a phenotype that resembles exhaustion. Conversely, overexpression of FOXO1 in mouse models of leukemia and bone cancer induced a gene expression program implicated in memory function and metabolic fitness and improved antitumor activity. The authors also show that FOXO1 expression positively correlates with CAR T cell persistence in the clinic.

CAR T 细胞疗法因这些细胞在体内耗尽而受到限制，尤其是在治疗实体瘤方面。积极的治疗反应与 T 细胞健康状况的改善有关，但尚不清楚哪些转录因子驱动这些健康计划。《自然》杂志上发表的两篇论文现已确定 FOXO1 是 CAR T 细胞功能的强大增强剂，可增强抗肿瘤活性、记忆力和代谢适应性。过度表达 FOXO1 可增强体内 T 细胞的效力，并使细胞更有效地对抗各种癌症，包括实体瘤。

尽管两个团队使用不同的方法来寻找改善治疗结果的转录因子，但都将 FOXO1 确定为主要调节因子。 Doan 及其同事表明，FOXO1 抑制会损害记忆基因的表达，使细胞获得类似于疲惫的表型。相反，在白血病和骨癌小鼠模型中，FOXO1 的过度表达会诱导与记忆功能和代谢适应性有关的基因表达程序，并提高抗肿瘤活性。作者还表明，FOXO1 表达与临床上 CAR T 细胞的持久性呈正相关。