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

Sep 30, 2026

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N-acetylcysteine (NAC) is a widely used antioxidant, yet its contribution to cancer progression has remained disputed and poorly resolved. In murine breast cancer metastasis models, systemic NAC markedly increased pulmonary metastasis without changing primary tumor growth in immunocompetent mice, while the effect disappeared in T cell-deficient animals. Mechanistically, NAC did not directly alter T cell or tumor cell behavior, but instead drove neutrophils toward an immunosuppressive program that inhibited T cell activation and effector functions. These findings indicate immune-mediated mechanisms for systemic antioxidant effects in cancer patients.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages15

Reading Time38 min

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Abstract

1. Introduction

2. Results

2.1. Antioxidant NAC Facilitates Lung Metastasis of Breast Cancer

Article Antioxidant N-Acetylcysteine Facilitates Breast Cancer Metas-Tasis via Immunosuppressive Reprogramming of Neutrophils Jiawen Zhang 1,2, Di Wang 2,3, Huige Wang 1,2, Qiuyu Wu 2,4, Menghao Liu 2,4, Qing Li 2, * and Zheng Gong 1,2,5, * Received: 22 November 2025 Revised: 26 December 2025 Accepted: 31 December 2025 Published: 4 January 2026 Copyright: © 2026 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license. 1 School of Basic Medical Sciences, Center for Big Data and Population Health of IHM, Anhui Medical University, Hefei 230032, China 2 Institute of Health and Medicine, Hefei Comprehensive National Science Center, Hefei 230601, China 3 Joint Research Center for Food Derived Functional Factors and Synthetic Biology of IHM, School of Food and Biological Engineering, Hefei University of Technology, Hefei 230009, China 4 Key Laboratory of Experimental Teratology, Ministry of Education, Institute of Molecular Medicine and Genetics, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan 250012, China 5 State Key Laboratory of Immune Response and Immunotherapy, Institute of Health and Medicine, Hefei Comprehensive National Science Center, Hefei 230027, China * Correspondence: [qing.li@ihm.ac.cn](qing.li@ihm.ac.cn) (Q.L.); [zheng.gong@ihm.ac.cn](zheng.gong@ihm.ac.cn) (Z.G.) 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 orthe 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. Keywords: N-acetylcysteine; lung metastasis; neutrophils; immunosuppression; breast cancer 1. Introduction Antioxidants are widely present in food, dietary supplements, and pharmaceuticals [1] . Through donating electrons, antioxidants can neutralize free radicals and reactive oxygen species (ROS) to prevent cellular damage and pro-tumorigenic signaling [2,3] . Numerous studies have demonstrated the anti-tumor effects of antioxidants in both in vitro and in vivo contexts, mainly by suppressing cell growth, promoting apoptosis, and inhibiting epithelial–mesenchymal transition [4–9] . However, this prevailing perspective has been challenged in recent years. Some studies have shown that antioxidants may exert tumorpromoting effects. For instance, low concentrations of vitamin C promoted the growth of melanoma cells [10] . Vitamin E accelerated tumor progression in a murine model of colorectal cancer [11] . A human clinical study revealed that participants receiving antioxidants had a significantly increased risk of prostate cancer [12] . By providing cysteine, NAC serves as a critical precursor in the biosy

FAQs

Does N-acetylcysteine (NAC) affect primary breast tumors in the described models?

Systemic NAC enhanced pulmonary metastasis without altering primary tumor growth in immunocompetent mice.

Is the metastasis-promoting effect of NAC dependent on T cells?

Yes. The property that promotes metastasis was abrogated in T cell-deficient mice, indicating a T cell-dependent mechanism.

How does NAC mechanistically promote breast cancer lung metastasis?

NAC educates neutrophils into an immunosuppressive phenotype, upregulating immunosuppressive genes and suppressing T cell activation and effector functions.

Sep 30, 2026

Uploaded by Stanford