Unlocking A Key Regulatory Factor In NK Cells—CREM

In the frontier field of cancer treatment, immunotherapy is gradually becoming a new hope for conquering cancer. In recent years, CAR-T cell therapy has achieved remarkable results in the treatment of blood tumors, but its application in the treatment of solid tumors still faces many challenges. At the same time, natural killer cells (NK cells), as an immune cell with strong anti-tumor activity, have gradually attracted the attention of researchers.

Recently, in a research report entitled "CREM is a regulatory checkpoint of CAR and IL-15 signalling in NK cells" published in the international journal Nature, scientists from the University of Texas MD Anderson Cancer Research Center and other institutions revealed a key regulatory factor in NK cells-CREM, which brought new hope to the development of CAR-NK cell therapy.

Although CAR-NK cell therapy has shown great potential in preclinical studies, the specific molecular mechanism of its functional regulation is still poorly understood. This study aims to further explore the molecular regulatory mechanism of CAR-NK cells to improve their anti-tumor effect.

In this study, the researchers mainly studied NK cells derived from human umbilical cord blood. These NK cells are genetically engineered to express CAR (chimeric antigen receptor) targeting specific tumor antigens. The study also involved a variety of human tumor cell lines, such as Raji (Burkitt's lymphoma), SKOV3 (ovarian cancer) and UMRC3 (renal cancer), to evaluate the anti-tumor activity of CAR-NK cells. In the experiment, the researchers used a variety of cutting-edge technologies including single-cell RNA sequencing (scRNA-seq), flow cytometry, mass spectrometry flow cytometry (CyTOF), chromatin immunoprecipitation sequencing (ChIP-seq) and gene editing technology (CRISPR-Cas9) to deeply analyze the role of CREM in NK cells from multiple levels such as gene expression, protein levels and epigenetics.

Figure 1. CREM is induced by CAR signalling and IL-15 stimulation. (Rafei, Hind, et al. 2025)

The researchers first used scRNA-seq technology to analyze the transcriptome changes of CAR-NK cells in the in vivo treatment model and found that the expression of CREM in CAR-NK cells was significantly upregulated and associated with cell activation and dysfunction. Using flow cytometry and CyTOF technology, the researchers detected the expression level of CREM in NK cells under different activation states and analyzed its correlation with cell function markers.

In addition, they also used CRISPR-Cas9 technology to knock out the CREM gene in NK cells to evaluate its effect on CAR-NK cell function. The experimental results showed that the expression of CREM was induced by CAR activation and IL-15 signals, and its upregulation was closely related to the activation and dysfunction of NK cells. After knocking out CREM by CRISPR-Cas9 technology, the anti-tumor activity of CAR-NK cells was significantly enhanced, showing higher cytotoxicity, stronger cytokine secretion ability and better in vivo anti-tumor effect.

The researchers also found that CREM can regulate the function of NK cells through epigenetic mechanisms. Knockout of CREM can change the chromatin state of NK cells. These findings not only reveal the important role of CREM in NK cells, but also provide new targets for the optimization of CAR-NK cell therapy.

This study deeply explored the regulatory role of CREM in CAR-NK cells and revealed its key role in NK cell activation and dysfunction. By knocking out CREM, the researchers successfully enhanced the anti-tumor activity of CAR-NK cells, providing new ideas and targets for the development of CAR-NK cell therapy. This discovery not only enriches our understanding of NK cell biology, but also opens up new directions for future cancer immunotherapy research.