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

Glutathione metabolism regulated by NRF2 promotes immune evasion and metastasis in breast cancer liver metastases, despite a highly immune-infiltrated microenvironment.

• Why it matters: Understanding how metastatic breast cancer cells evade immune destruction in the liver can inform new therapeutic strategies to prevent or treat metastasis, addressing a major clinical challenge.
• What they did: Single-cell transcriptomic sequencing of matched primary tumors and liver metastases from 13 treatment-naïve patients revealed that metastatic cells maintain genomic diversity but adapt metabolically through elevated glutathione (GSH) metabolism linked to NRF2 activity, which promotes tumor stemness and suppresses CD8+ T cell responses.
• The result: Inhibiting NRF2 and GSH reduced liver metastasis and enhanced antitumor immunity, suggesting that targeting tumor-intrinsic metabolic pathways may restore immune surveillance and serve as a promising therapeutic approach.