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

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: 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.