美国德克萨斯大学David Marin研究团队报道了CREM是NK细胞中CAR和IL-15信号的调控检查点。该研究于2025年6月4日发表于国际一流学术期刊《自然》杂志上。

在这里，该研究团队确定了转录因子环AMP响应元件调制器（CREM）作为NK细胞功能的关键调节器。转录组学分析显示，在肿瘤motheme模型中过继转移后，CAR-NK细胞在效应功能高峰期间显著诱导CREM，并且该高峰与激活和功能障碍的特征一致。研究团队证明了CAR激活和白细胞介素-15信号传导都能快速诱导NK细胞的CREM上调。在功能上，CREM缺失增强了CAR-NK细胞在体外和体内的效应功能，并增加了对肿瘤诱导的免疫抑制的抵抗。在机制上，该团队确定了CREM的诱导是由PKA-CREB信号通路介导的，该信号通路可以被CAR激活下游的基于免疫受体酪氨酸的激活基序信号或白细胞介素-15激活。最后，他们的发现揭示了CREM通过CAR-NK细胞的表观遗传重编程发挥其调节功能。这些结果为CREM作为一种治疗靶点来增强CAR-NK细胞的抗肿瘤功效提供了支持。

据了解，嵌合抗原受体（CAR）自然杀伤（NK）细胞免疫治疗提供了一种很有前途的治疗癌症的方法。然而，调节CAR-NK细胞活性的分子机制尚不清楚。

附：英文原文

Title: CREM is a regulatory checkpoint of CAR and IL-15 signalling in NK cells

Author: Rafei, Hind, Basar, Rafet, Acharya, Sunil, Hsu, Yu-Sung, Liu, Pinghua, Zhang, Deqiang, Bohn, Toszka, Liang, Qingnan, Mohanty, Vakul, Upadhyay, Ranjan, Li, Ping, Phadatare, Pravin, Dede, Merve, Xiong, Donghai, Fan, Huihui, Jones, Corry Mathew, Kunz, Sebastian, Daher, May, Nunez Cortes, Ana Karen, Shanley, Mayra, Liu, Bin, Moseley, Sadie Mae, Zhang, Chenyu, Fang, Dexing, Banerjee, Pinaki, Uprety, Nadima, Li, Ye, Shrestha, Rejeena, Wan, Xinhai, Shen, Hong, Woods, Vernikka, Gilbert, April Lamour, Rawal, Seema, Dou, Jinzhuang, Tan, Yukun, Park, Jeong-Min, Reyes Silva, Francia, Biederstdt, Alexander, Kaplan, Mecit, Jiang, Xin Ru, Biederstdt, Inci, Kumar, Bijender, Tiberti, Silvia, Moore, Madison, Jin, Jingling, Yang, Ryan Z., Muniz-Feliciano, Luis, Rosemore, Samuel, Lin, Paul, Deyter, Gary M., Fowlkes, Natalie Wall, Jain, Abhinav K., Marin, David

Issue&Volume: 2025-06-04

Abstract: Chimeric antigen receptor (CAR) natural killer (NK) cell immunotherapy offers a promising approach against cancer1,2,3. However, the molecular mechanisms that regulate CAR-NK cell activity remain unclear. Here we identify the transcription factor cyclic AMP response element modulator (CREM) as a crucial regulator of NK cell function. Transcriptomic analysis revealed a significant induction of CREM in CAR-NK cells during the peak of effector function after adoptive transfer in a tumour mouse model, and this peak coincided with signatures of both activation and dysfunction. We demonstrate that both CAR activation and interleukin-15 signalling rapidly induce CREM upregulation in NK cells. Functionally, CREM deletion enhances CAR-NK cell effector function both in vitro and in vivo and increases resistance to tumour-induced immunosuppression after rechallenge. Mechanistically, we establish that induction of CREM is mediated by the PKA–CREB signalling pathway, which can be activated by immunoreceptor tyrosine-based activation motif signalling downstream of CAR activation or by interleukin-15. Finally, our findings reveal that CREM exerts its regulatory functions through epigenetic reprogramming of CAR-NK cells. Our results provide support for CREM as a therapeutic target to enhance the antitumour efficacy of CAR-NK cells.

DOI: 10.1038/s41586-025-09087-8

Source: https://www.nature.com/articles/s41586-025-09087-8