# Antioxidant N-Acetylcysteine Facilitates Breast Cancer Metas-Tasis via Immunosuppressive Reprogramming of Neutrophils

## TL;DR

N-Acetylcysteine, an antioxidant, promotes breast cancer spread to the lungs by altering neutrophils to suppress immune responses.

## Contribution

NAC promotes breast cancer metastasis by reprogramming neutrophils to suppress T cell immunity.

## Key findings

- NAC enhances pulmonary metastasis in immunocompetent mice but not in T cell-deficient mice.
- NAC reprograms neutrophils to an immunosuppressive phenotype that inhibits T cell function.
- NAC's effect is not due to direct impacts on T cells or tumor cells.

## Abstract

N-acetylcysteine (NAC) is a widely used antioxidant. It has also attracted significant research interest with regard to its role in cancer progression, although the mechanisms involved remain controversial and poorly understood. Here, using murine models of breast cancer metastasis, we found that systemic NAC administration significantly enhanced pulmonary metastasis without altering primary tumor growth in immunocompetent mice, whereas this metastasis-promoting property of NAC was abrogated in T cell-deficient mice. This phenomenon was not due to the direct effects of NAC on T cells or tumor cells, since in vitro studies indicated that NAC exhibited no impact on the effector functions of T cells or the malignant behavior of breast cancer cells. Mechanistically, we demonstrated that NAC endows neutrophils with an immunosuppressive phenotype, which is characterized by the upregulation of immunosuppressive genes, and these NAC-educated neutrophils potently suppress the activation and effector functions of T cells. Collectively, our study reveals a previously unrecognized role played by NAC in regulating breast cancer lung metastasis by orchestrating the myeloid-dependent suppression of anti-tumor T cell immunity and suggests a need to consider immune-mediated mechanisms when evaluating the systemic impact of antioxidant agents in cancer patients.