Neutrophils Disable NK Cells to Fuel Breast Cancer Liver Metastasis

Neutrophils accumulating in the liver during breast cancer metastasis can suppress natural killer cells by stripping them of key transcription factors, according to a study published in Breast Cancer Research on 24 September 2026. The open-access paper, led by Yunyun Shen and Peter M. Siegel, describes a contact-dependent mechanism in which neutrophils isolated from metastasis-bearing mice drive downregulation of Eomes and T-bet, two regulators of NK cell maturation and effector function, ultimately impairing the ability of NK cells to kill tumor cells.

Metastatic disease remains the primary cause of cancer-related mortality, and immune evasion is a critical barrier to clearing disseminated tumor cells. NK cells are cytotoxic lymphocytes that contribute to early immune surveillance of metastases, but their function is often impaired in solid tumors. Neutrophils, the most abundant circulating leukocytes, have emerged as context-dependent regulators of tumor progression and immune suppression. While crosstalk between neutrophils and NK cells has been implicated in shaping anti-tumor immunity, the mechanisms by which neutrophils modulate NK cell function have remained poorly defined.

To probe this relationship, the team used a syngeneic triple-negative breast cancer mouse model of liver metastasis. In this model, they investigated the immunoregulatory role of neutrophils in modulating NK cell activity, focusing on how neutrophils recovered from breast cancer liver metastases affected NK cells when the two cell types were co-cultured in the laboratory.

The results showed that neutrophils accumulate in the metastatic liver and progressively outnumber NK cells as the breast cancer liver metastases grow. This shift in the local immune landscape suggested that neutrophils could be actively reshaping the environment in which NK cells operate, rather than merely appearing alongside them.

When neutrophils isolated from metastasis-bearing mice were co-cultured with NK cells, the researchers measured the expression of key NK transcription factors. The neutrophils induced downregulation of Eomes and T-bet, and they did so through a mechanism that required contact between the two cell types. The co-culture also reduced NK-mediated tumor cell killing, directly linking the transcriptional changes to a functional loss of cytotoxic capacity.

NK cells taken from metastasis-bearing mice themselves exhibited hallmarks of functional exhaustion. These included reduced expression of activating receptors and elevated expression of inhibitory receptors, a receptor pattern consistent with NK cells being held in a suppressed state rather than simply being depleted from the tissue.

The authors conclude that these findings uncover a previously unrecognized component of neutrophil-mediated NK cell suppression in breast cancer liver metastasis, directly linking neutrophil-NK interaction with reduced Eomes and T-bet expression within NK cells and impaired NK cell-mediated tumor killing. They add that the work provides mechanistic insight into the limited efficacy of NK cell-based immunotherapies in solid tumors, where the microenvironment may undermine transferred or endogenous NK cells before they can act.

According to the paper, targeting neutrophil-NK cell interactions may represent a promising therapeutic strategy to restore innate immune function and limit metastatic outgrowth. The authors frame this as a direction for future work rather than a demonstrated treatment, since the study’s conclusions rest on a mouse model and ex vivo co-culture experiments.

As with any preclinical study, the findings are bounded by their scope. The experiments were conducted in a single syngeneic triple-negative breast cancer model, and the neutrophil effects were characterized in isolated cells rather than through a therapeutic intervention in animals or patients. The article is being shared early as a peer-reviewed, accepted manuscript that carries a permanent DOI and is citable, with a final Version of Record to follow after further edits. Even so, the study offers a concrete mechanistic account of how an abundant innate immune cell can quietly disarm one of the body’s first lines of defense against metastatic seeding in the liver.

Subject of Research: Neutrophil-mediated suppression of NK cell function in breast cancer liver metastasis

Article Title: Neutrophil-mediated NK cell dysfunction via Eomes and T-bet suppression promotes breast cancer liver metastasis

Article References: Shen, Y., Hsu, B. E., Solymoss, E., Feng, C.-H., Tabariès, S., Annis, M. G., Fois, A., Shen, M. L., Duerr, C. U., Fritz, J. H., Tremblay, M. L., Lesage, S., & Siegel, P. M. (2026). Neutrophil-mediated NK cell dysfunction via Eomes and T-bet suppression promotes breast cancer liver metastasis. Breast Cancer Research. https://doi.org/10.1186/s13058-026-02379-5

Image Credits: AI Generated

DOI: 10.1186/s13058-026-02379-5

Keywords: breast cancer, liver metastasis, neutrophils, NK cells, Eomes, T-bet, immune suppression, tumor immunology, triple-negative breast cancer, immune evasion, cytotoxicity, tumor microenvironment