# The CHI3L1-neutrophil axis drives immune suppression and breast cancer metastatic dissemination

## TL;DR

This study shows how the CHI3L1 protein promotes breast cancer metastasis by recruiting neutrophils and suppressing the immune system.

## Contribution

The study identifies a novel CHI3L1-neutrophil axis that drives immune suppression and metastasis in breast cancer.

## Key findings

- CHI3L1 overexpression in breast cancer suppresses antitumor immunity and accelerates tumor growth.
- CHI3L1 recruits neutrophils that degrade the extracellular matrix and increase circulating tumor cells.
- Targeting CHI3L1 could enhance immunity and reduce metastasis in breast cancer.

## Abstract

Immunosuppression and metastasis are critical hallmarks of breast cancer, often linked to poor patient outcomes. The secreted cytokine chitinase-3–like 1 (CHI3L1) is frequently overexpressed in breast cancer samples and promotes an immunosuppressed tumor microenvironment. Notably, CHI3L1 expression is elevated in metastatic patient samples when compared with the matched primary breast tumor. To investigate its role in breast cancer metastasis, we generated an inducible genetically engineered mouse model that overexpresses CHI3L1 in the mammary epithelium. Ectopic expression of CHI3L1 in the polyomavirus middle T (PyMT) mouse model of breast cancer suppressed antitumor immune responses, accelerated mammary tumor onset, and enhanced lung metastasis. Mechanistically, elevated CHI3L1 expression in the mammary epithelium enhanced neutrophil recruitment, which subsequently degraded the extracellular matrix and increased the number of circulating tumor cells. These findings reveal a key mechanism driving metastatic dissemination and argue that therapeutically targeting Chi3l1 could enhance antitumor immunity and suppress metastasis.

Metastasis is the leading cause of breast cancer mortality. We demonstrate that STAT3-induced Chi3l1 recruits neutrophils that break extracellular matrix barriers, enabling cancer spread.