Faculty, Staff and Student Publications

Publication Date

7-1-2025

Journal

Nature

DOI

10.1038/s41586-025-09087-8

PMID

40468083

PMCID

PMC12286855

PubMedCentral® Posted Date

6-4-2025

PubMedCentral® Full Text Version

Nature

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.

Keywords

Animals, Interleukin-15, Killer Cells, Natural, Mice, Signal Transduction, Cyclic AMP Response Element Modulator, Receptors, Chimeric Antigen, Cyclic AMP Response Element-Binding Protein, Cyclic AMP-Dependent Protein Kinases, Humans, Female, Male, Epigenesis, Genetic, Immunotherapy, Adoptive, Mice, Inbred C57BL, Up-Regulation

Published Open-Access

yes

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