Related Experiment Video

Updated: Sep 19, 2025

Natural Killer NK and CAR-NK Cell Expansion Method using Membrane Bound-IL-21-Modified B Cell Line
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CREM is a regulatory checkpoint of CAR and IL-15 signalling in NK cells

Hind Rafei1,2, Rafet Basar1,2, Sunil Acharya1,2

  • 1Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Nature
|June 4, 2025
PubMed

Insights

Cyclic AMP response element modulator (CREM) regulates chimeric antigen receptor (CAR) natural killer (NK) cell function. Targeting CREM enhances CAR-NK cell efficacy against tumors.

Area of Science:

  • Immunology
  • Cell Biology
  • Cancer Research

Background:

  • Chimeric antigen receptor (CAR) natural killer (NK) cell immunotherapy shows promise for cancer treatment.
  • The molecular mechanisms governing CAR-NK cell activity and potential dysfunction are not fully understood.

Purpose of the Study:

  • To identify key regulators of CAR-NK cell function.
  • To elucidate the role of the transcription factor cyclic AMP response element modulator (CREM) in CAR-NK cell activity.
  • To explore CREM as a potential therapeutic target for enhancing anti-cancer immunity.

Main Methods:

  • Transcriptomic analysis of CAR-NK cells in a tumor mouse model.
  • Investigating CREM induction via CAR activation and interleukin-15 signaling.
  • Assessing the impact of CREM deletion on CAR-NK cell function in vitro and in vivo.
  • Elucidating the PKA-CREB signaling pathway mediating CREM induction.
  • Analyzing CREM's epigenetic reprogramming effects on CAR-NK cells.

Main Results:

  • CREM is significantly upregulated in CAR-NK cells during peak effector function, coinciding with activation and dysfunction signatures.
  • Both CAR activation and IL-15 signaling rapidly induce CREM.
  • CREM deletion enhances CAR-NK cell effector functions and resistance to tumor-induced immunosuppression.
  • CREM induction is mediated by the PKA-CREB pathway.
  • CREM regulates CAR-NK cell function through epigenetic reprogramming.

Conclusions:

  • CREM is a critical regulator of CAR-NK cell function, influencing both activation and dysfunction.
  • Targeting CREM presents a viable strategy to improve the anti-tumor efficacy of CAR-NK cell immunotherapy.

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