Paired Single-Cell Profiling Reveals Glutathione-Dependent Immune Evasion in Breast Cancer Liver Metastasis.

Authors

Cheng Lyu, Meiqi Wang, Haitao Wang, Yixin Qi, Bizhu Chu, Xiaohui Ji, Cuizhi Geng, Zepeng Hou, Lan Jin, Shengnan Guo, Tianhao Li, Dapeng Hao, Zhenchuan Song

Published in

Cancer research. Oct 08, 2026. Epub Oct 08, 2026.

Abstract

Breast cancer liver metastasis (BCLM) represents a major clinical challenge. Characterizing the differences between primary and metastatic tumors could help identify therapeutic targets for preventing and treating metastasis. Through single-cell transcriptomic sequencing of matched primary tumors and BCLMs from 13 treatment-naïve patients, we uncovered a fundamental paradox in metastatic progression: BCLMs exhibited a highly immune-infiltrated microenvironment characterized by cytotoxic T cell expansion, inflammatory macrophage polarization, and depletion of regulatory T cells, yet they successfully evaded immune-mediated destruction. Metastatic cells retained extensive clonal and genomic diversity from their primary tumors, suggesting a polyclonal metastatic process rather than a stringent metastatic "bottleneck". Instead, cancer cells featured a metabolic adaptation mechanism in which elevated glutathione (GSH) metabolism in the liver fosters glutamine addiction, creating liver metastasis susceptibility. Integrative regulatory network analyses pinpointed NRF2 as a key regulator associated with GSH metabolism, and functional experiments demonstrated that GSH promoted tumor stemness and attenuated CD8⁺ T cell-mediated antitumor immunity in an NRF2-dependent manner. Inhibition of NRF2 and GSH reduced liver metastasis in vivo and was associated with enhanced antitumor immune responses. Together, this study provides comprehensive single-cell characterization of the immune-metabolic landscape in treatment-naïve BCLM and reveals a potential model in which metastatic success in immune-competent tissues depends on tumor cell-intrinsic metabolic adaptation. These findings provide insights into breast cancer liver metastatic progression and suggest NRF2 and GSH inhibition as a promising therapeutic strategy that could restore immune surveillance in liver metastases.

PMID:
42848958
Bibliographic data and abstract were imported from PubMed on 09 Oct 2026.

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