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

Hind Rafei, Rafet Basar, Sunil Acharya, Yu-Sung Hsu, Pinghua Liu, Deqiang Zhang, Toszka Bohn, Qingnan Liang, Vakul Mohanty, Ranjan Upadhyay, Ping Li, Pravin Phadatare, Merve Dede, Donghai Xiong, Huihui Fan, Corry Mathew Jones, Sebastian Kunz, May Daher, Ana Karen Nunez Cortes, Mayra Shanley, Bin Liu, Sadie Mae Moseley, Chenyu Zhang, Dexing Fang, Pinaki Banerjee, Nadima Uprety, Ye Li, Rejeena Shrestha, Xinhai Wan, Hong Shen, Vernikka Woods, April Lamour Gilbert, Seema Rawal, Jinzhuang Dou, Yukun Tan, Jeong-Min Park, Francia Reyes Silva, Alexander Biederstädt, Mecit Kaplan, Xin Ru Jiang, Inci Biederstädt, Bijender Kumar, Silvia Tiberti, Madison Moore, Jingling Jin, Ryan Z. Yang, Luis Muniz-Feliciano, Samuel Rosemore, Paul Lin, Gary M. Deyter, Natalie Wall Fowlkes, Abhinav K. Jain, David Marin, Anirban Maitra, Ken Chen, Tobias Bopp, Elizabeth J. Shpall and Katayoun Rezvani ()
Additional contact information
Hind Rafei: The University of Texas MD Anderson Cancer Center
Rafet Basar: The University of Texas MD Anderson Cancer Center
Sunil Acharya: The University of Texas MD Anderson Cancer Center
Yu-Sung Hsu: The University of Texas MD Anderson Cancer Center
Pinghua Liu: The University of Texas MD Anderson Cancer Center
Deqiang Zhang: The University of Texas MD Anderson Cancer Center
Toszka Bohn: University Medical Center of the Johannes Gutenberg University
Qingnan Liang: The University of Texas MD Anderson Cancer Center
Vakul Mohanty: The University of Texas MD Anderson Cancer Center
Ranjan Upadhyay: The University of Texas MD Anderson Cancer Center
Ping Li: The University of Texas MD Anderson Cancer Center
Pravin Phadatare: The University of Texas MD Anderson Cancer Center
Merve Dede: The University of Texas MD Anderson Cancer Center
Donghai Xiong: The University of Texas MD Anderson Cancer Center
Huihui Fan: University of Texas Health Science Center at Houston
Corry Mathew Jones: The University of Texas MD Anderson Cancer Center
Sebastian Kunz: University Medical Center of the Johannes Gutenberg University
May Daher: The University of Texas MD Anderson Cancer Center
Ana Karen Nunez Cortes: The University of Texas MD Anderson Cancer Center
Mayra Shanley: The University of Texas MD Anderson Cancer Center
Bin Liu: The University of Texas MD Anderson Cancer Center
Sadie Mae Moseley: The University of Texas MD Anderson Cancer Center
Chenyu Zhang: The University of Texas MD Anderson Cancer Center
Dexing Fang: The University of Texas MD Anderson Cancer Center
Pinaki Banerjee: The University of Texas MD Anderson Cancer Center
Nadima Uprety: The University of Texas MD Anderson Cancer Center
Ye Li: The University of Texas MD Anderson Cancer Center
Rejeena Shrestha: The University of Texas MD Anderson Cancer Center
Xinhai Wan: The University of Texas MD Anderson Cancer Center
Hong Shen: The University of Texas MD Anderson Cancer Center
Vernikka Woods: The University of Texas MD Anderson Cancer Center
April Lamour Gilbert: The University of Texas MD Anderson Cancer Center
Seema Rawal: The University of Texas MD Anderson Cancer Center
Jinzhuang Dou: The University of Texas MD Anderson Cancer Center
Yukun Tan: The University of Texas MD Anderson Cancer Center
Jeong-Min Park: The University of Texas MD Anderson Cancer Center
Francia Reyes Silva: The University of Texas MD Anderson Cancer Center
Alexander Biederstädt: The University of Texas MD Anderson Cancer Center
Mecit Kaplan: The University of Texas MD Anderson Cancer Center
Xin Ru Jiang: The University of Texas MD Anderson Cancer Center
Inci Biederstädt: The University of Texas MD Anderson Cancer Center
Bijender Kumar: The University of Texas MD Anderson Cancer Center
Silvia Tiberti: The University of Texas MD Anderson Cancer Center
Madison Moore: The University of Texas MD Anderson Cancer Center
Jingling Jin: The University of Texas MD Anderson Cancer Center
Ryan Z. Yang: The University of Texas MD Anderson Cancer Center
Luis Muniz-Feliciano: The University of Texas MD Anderson Cancer Center
Samuel Rosemore: The University of Texas MD Anderson Cancer Center
Paul Lin: The University of Texas MD Anderson Cancer Center
Gary M. Deyter: The University of Texas MD Anderson Cancer Center
Natalie Wall Fowlkes: The University of Texas MD Anderson Cancer Center
Abhinav K. Jain: The University of Texas MD Anderson Cancer Center
David Marin: The University of Texas MD Anderson Cancer Center
Anirban Maitra: The University of Texas MD Anderson Cancer Center
Ken Chen: The University of Texas MD Anderson Cancer Center
Tobias Bopp: University Medical Center of the Johannes Gutenberg University
Elizabeth J. Shpall: The University of Texas MD Anderson Cancer Center
Katayoun Rezvani: The University of Texas MD Anderson Cancer Center

Nature, 2025, vol. 643, issue 8073, 1076-1086

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41586-025-09087-8

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