Tumor-associated neutrophils drive liver-specific metastatic progression in breast cancer through methionine metabolism mediated by methionine adenosyltransferase II alpha

Sep 30, 2026

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Breast cancer displays pronounced organotropism toward the liver, yet the biological basis of this liver-specific metastatic progression remains incompletely defined. This study investigates how tumor microenvironment metabolic regulation, focusing on tumor-associated neutrophils (TANs), shapes breast cancer liver metastasis. Using bioinformatic immune and clinical validations, metabolomics, and functional in vitro experiments, the work identifies a neutrophil-enriched microenvironment that activates methionine metabolism via MAT2A, enabling stemness and chemoresistance. Pharmacological MAT2A inhibition reverses TAN-driven tumorigenic phenotypes and supports a TAN-MAT2A-methionine axis as a therapeutic target.

LanguageEnglish

CategoryHealthcare

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Pages16

Reading Time40 min

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Tumor-associated neutrophils drive liver-specific metastatic progression in breast cancer through methionine metabolism mediated by methionine adenosyltransferase II alpha Lifeng Huang1\#, Shuang Zhen 1\#, Qi Wang2\#, Yue Sun3, Tian Ji1, Rui Chen1, Jue Wang1, Qiannan Zhu 1, Dongwei Xu4, Xiaoming Zha1 1Department of General Surgery, The First Affiliated Hospital with Nanjing Medical University, Nanjing, China; 2Department of Pathology, The First Affiliated Hospital with Nanjing Medical University, Nanjing, China; 3Department of Oncology, The First Affiliated Hospital with Nanjing Medical University, Nanjing, China; 4Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China Contributions: (I) Conception and design: L Huang, S Zhen; (II) Administrative support: Q Zhu, D Xu, X Zha; (III) Provision of study materials or patients: Q Wang, Y Sun, T Ji; (IV) Collection and assembly of data: Q Wang, T Ji; (V) Data analysis and interpretation: R Chen, J Wang; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors. \#These authors contributed equally to this work. Correspondence to: Dr. Xiaoming Zha, MD. Department of General Surgery, The First Affiliated Hospital with Nanjing Medical University, 300 Guangzhou Road, Nanjing 210029, China. Email: [njzhaxm@njmu.edu.cn](njzhaxm@njmu.edu.cn); Dr. Dongwei Xu, PhD, Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 160 Pujian Road, Shanghai 200127, China. Email: [xudongwei21@126.com](xudongwei21@126.com); Dr. Qiannan Zhu, MD. Department of General Surgery, The First Affiliated Hospital with Nanjing Medical University, 300 Guangzhou Road, Nanjing 210029, China. Email: [zhuqiannan1989@outlook.com](zhuqiannan1989@outlook.com). Background: The mechanisms underlying the pronounced organotropism of breast cancer (BC) for the liver remain incompletely elucidated. This study aims to investigate the role of the tumor microenvironment (TME), particularly tumor-associated neutrophils (TANs), and their metabolic regulation in breast cancer liver metastasis (BCLM) . Methods: We employed a multi-level integrative approach. Bioinformatic analysis of Gene Expression Omnibus (GEO) datasets characterized the immune landscape of BCLM. Clinical specimens, and in vitro assays were utilized to define the functional interplay between TANs and BC cells. Metabolomic profiling of patient samples was conducted to characterize metabolic alterations in BCLM. Results: A neutrophil-enriched TME was identified as a distinct feature of BCLM. Functional studies demonstrated that TANs enhance cancer stemness and chemoresistance by upregulating methionine adenosyltransferase II alpha (MAT2A), a key enzyme that activates methionine metabolism. What is more, pharmacological inhibition of MAT2A successfully reversed the pro-tumorigenic phenotypes induced by TANs. Metabolomic analysis of patient specimens provided direct clinical evidence for the specific activation of the methionine cycle in BCLM tissues. Conclusions: Our work uncovers a neutrophil-driven, MAT2A-dependent activation of methionine metabolism as a critical metabolic mechanism fueling liver metastasis in BC. These findings position the TAN-MAT2A-methionine axis as a promising therapeutic target for the treatment of BCLM. Keywords: Breast cancer (BC); liver metastasis; tumor-associated neutrophils (TANs); methionine metabolism; cancer stemness Submitted Oct 21, 2025. Accepted for publication Dec 09, 2025. Published online Dec 29, 2025. doi: 10.21037/tcr-2025-aw-2278 View this article at: [https://dx.doi.org/10.21037/tcr-2025-aw-2278](https://dx.doi.org/10.21037/tcr-2025-aw-2278) © AME Publishing Company. Transl Cancer Res 2025;14(12):8949-8964 | [https://dx.doi.org/10.21037/tcr-2025-aw-2278](https://dx.doi.org/10.21037/tcr-2025-aw-2278) 8950 Huang et al. Neutrophil methionine in BCLM Introduction

FAQs

What role do tumor-associated neutrophils (TANs) play in breast cancer liver metastasis?

The study shows TANs enrich the tumor microenvironment and promote cancer stemness and chemoresistance in breast cancer cells.

How is methionine metabolism linked to TAN-driven metastasis?

TANs upregulate methionine adenosyltransferase II alpha (MAT2A), activating methionine metabolism and supporting liver colonization and therapy resistance.

What is the effect of inhibiting MAT2A?

Pharmacological inhibition of MAT2A reverses pro-tumorigenic phenotypes induced by TANs and provides mechanistic support for MAT2A as a target.

Sep 30, 2026

Uploaded by Connor