Neutrophils are the body’s frontline defense against pathogens. They are the most abundant type of immune cell in the human body, particularly in the bloodstream, where they make up about 50–70% of all circulating white blood cells. Like other innate immune cells, such as macrophages, they also play various roles in cancer, depending on their functional states. Their abundance in tumors has long been associated with poor patient prognosis. On the other hand, the cells can be key supporters of anti-tumor immunity. In a pair of studies published this summer, researchers co-led by Ludwig Weill Cornell Medicine’s Taha Merghoub and Tao Shi with colleagues at Nanjing University in China detailed two distinct ways in which immature neutrophils suppress anti-tumor immune responses and immunotherapy in both primary tumors and metastatic bone lesions.
Tao, Taha and colleagues reported in an August publication in Cancer Cell that neutrophils in bone metastases, which are notoriously resistant to therapy, are reprogrammed into an immature state in which they suppress anti-tumor immunity. This is accomplished by a protein churned out by bone metastases, DKK1, that prompts functionally immature neutrophils to produce CHI3L3, which disrupts the activation and function of the CD8+ T effector cells. The elevated levels of DKK1 seen in mouse models were consistent with analyses of patient data and in serum samples obtained from gastric cancer patients with bone metastases. The researchers identified the biochemical signaling cascade activated by DKK1 that reprograms neutrophils. They also showed that DKK1 blockade—for which an antibody is currently in early clinical trials—restores the sensitivity of bone metastases to immunotherapy in mouse models, suggesting a combination with immune based therapies. Beyond that, CHI3L3 and the signature of gene expression it triggers could serve as biomarkers to identify patients with high neutrophil-mediated immune suppression and better tailor treatments to their tumors.
In the other study, reported in a July issue of Cell Research, Tao, Taha and colleagues identified separate precursors of neutrophils—specifically, myelocyte and metamyelocyte (MC & MM) stages of the developing immune cells—in human bone marrow that suppress anti-tumor immunity and drive cancer progression. These immature cells constitute the majority of neutrophils that infiltrate tumors across 17 types of cancer. The researchers showed that in mice with human immune systems, MC & MM are the majority of neutrophils in tumors. They also identified biomarkers to detect these cells in cancer patients and showed that their expression is associated with worse prognoses. The researchers preclinically demonstrated a strategy to trans-differentiate MC & MM-stage neutrophils into monocytic cells as a potential cancer therapy.
CHI3L3+ immature neutrophils inhibit anti-tumor immunity and impede immune checkpoint blockade therapy in bone metastases
Cancer Cell, 2025 August 7
Human myelocyte and metamyelocyte-stage neutrophils suppress tumor immunity and promote cancer progression
Cell Research, 2025 July 15