%0 Journal Article
%A Rafei, Hind
%A Basar, Rafet
%A Acharya, Sunil
%A Hsu, Yu-Sung
%A Liu, Pinghua
%A Zhang, Deqiang
%A Bohn, Toszka
%A Liang, Qingnan
%A Mohanty, Vakul
%A Upadhyay, Ranjan
%A Li, Ping
%A Phadatare, Pravin
%A Dede, Merve
%A Xiong, Donghai
%A Fan, Huihui
%A Jones, Corry Mathew
%A Kunz, Sebastian
%A Daher, May
%A Nunez Cortes, Ana Karen
%A Shanley, Mayra
%A Liu, Bin
%A Moseley, Sadie Mae
%A Zhang, Chenyu
%A Fang, Dexing
%A Banerjee, Pinaki
%A Uprety, Nadima
%A Li, Ye
%A Shrestha, Rejeena
%A Wan, Xinhai
%A Shen, Hong
%A Woods, Vernikka
%A Gilbert, April Lamour
%A Rawal, Seema
%A Dou, Jinzhuang
%A Tan, Yukun
%A Park, Jeong-Min
%A Reyes Silva, Francia
%A Biederstädt, Alexander
%A Kaplan, Mecit
%A Jiang, Xin Ru
%A Biederstädt, Inci
%A Kumar, Bijender
%A Tiberti, Silvia
%A Moore, Madison
%A Jin, Jingling
%A Yang, Ryan Z
%A Muniz-Feliciano, Luis
%A Rosemore, Samuel
%A Lin, Paul
%A Deyter, Gary M
%A Fowlkes, Natalie Wall
%A Jain, Abhinav K
%A Marin, David
%A Maitra, Anirban
%A Chen, Ken
%A Bopp, Tobias
%A Shpall, Elizabeth J
%A Rezvani, Katayoun
%T CREM is a regulatory checkpoint of CAR and IL-15 signalling in NK cells.
%J Nature
%V 643
%N 8073
%@ 0028-0836
%C London [u.a.]
%I Nature Publ. Group
%M DKFZ-2025-01150
%P 1076-1086
%D 2025
%Z 2025 Jul;643(8073):1076-1086
%X Chimeric antigen receptor (CAR) natural killer (NK) cell immunotherapy offers a promising approach against cancer1-3. 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.
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:40468083
%R 10.1038/s41586-025-09087-8
%U https://inrepo02.dkfz.de/record/301770