Bromodomain and extra-terminal protein inhibitors modulate natural killer cell function and differentiation.

Creator(s)

Eric S. Geanes, Children's Mercy HospitalFollow
Gage Greening, Children's Mercy Kansas CityFollow
Maria Aggelakopoulou
Linh Huyen Truong
Santosh Khanal, Children's Mercy HospitalFollow
Cas LeMaster, Children's Mercy HospitalFollow
Marc L. Herman, Children's Mercy Kansas CityFollow
Rebecca McLennan, Children's Mercy HospitalFollow
Persephone Borrow
Todd Bradley, Children's Mercy HospitalFollow

Document Type

Article

Publication Date

1-3-2026

Identifier

DOI: 10.1038/s41598-025-33437-1; PMCID: PMC12835054

Abstract

Natural killer (NK) cells are integral to the innate immune system, playing a crucial role in immune surveillance and the rapid response to virally infected and tumor cells. Epigenetic gene expression regulation significantly influences NK cell function and differentiation. Using a high-throughput small-molecule drug screening approach, we identified bromodomain and extra-terminal domain (BET) inhibitors (BETi) as potent modulators of NK cell function, reducing proinflammatory cytokine secretion while increasing markers of NK cell maturation and cytotoxicity. During NK lineage specification from hematopoietic stem cells, we demonstrated that BETi reduced NK cell fate and promoted increased myeloid cell differentiation. Moreover, differentiated NK cell types had more functionally differentiated gene expression programs. Thus, BET proteins are crucial for both mature NK cell functions and controlling NK cell lineage development from progenitors in the bone marrow. These findings suggest that BETi can fine-tune NK cell responses, offering promising therapeutic potential for cancer immunotherapy and the treatment of inflammatory and autoimmune diseases. Our study underscores the critical role of BET inhibitors in regulating NK cell function and opens new avenues for targeted immune modulation.

Journal Title

Sci Rep

Volume

16

Issue

1

First Page

3465

Last Page

3465

MeSH Keywords

Killer Cells, Natural; Cell Differentiation; Humans; Animals; Cell Lineage; Cytokines; Mice; Hematopoietic Stem Cells; Proteins; Bromodomain Containing Proteins

PubMed ID

41484412

Keywords

Epigenetic regulation; Innate immunity; Natural killer cells; Single-cell genomics

Comments

Grants and funding

• R01 AI 147778/NIH, NIAID, DAIDS
• UM1 AI 144371/Consortium for HIV/AIDS Vaccine Development
• UM1 AI 164567/Martin Delaney Collaboratory of AIDS Researchers for Eradication

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Publisher's Link: https://www.nature.com/articles/s41598-025-33437-1

Recommended Citation

Geanes ES, Greening G, Aggelakopoulou M, et al. Bromodomain and extra-terminal protein inhibitors modulate natural killer cell function and differentiation. Sci Rep. 2026;16(1):3465. Published 2026 Jan 3. doi:10.1038/s41598-025-33437-1