Hydrogen Sulfide Promotes TAM-M1 Polarization through Activating IRE-1α Pathway via GRP78 S-Sulfhydrylation to...

Area of Science:

• Biochemistry
• Immunology
• Oncology

Background:

• Protein S-sulfhydration, mediated by hydrogen sulfide (H2S), is crucial in disease.
• Tumor-associated macrophages (TAMs) suppress anti-tumor immunity in solid tumors.
• The role of S-sulfhydration in breast cancer TAM reprogramming remains unexplored.

Purpose of the Study:

• To investigate if protein S-sulfhydration regulates TAM reprogramming in breast cancer (BC).
• To elucidate the underlying molecular mechanisms of S-sulfhydration in BC-TAMs.

Main Methods:

• Correlation analysis of the CTH-H2S axis with TAM phenotype in BC.
• In vitro and in vivo experiments using NaHS (H2S donor) to repolarize TAMs.
• Mechanistic studies involving S-sulfhydration of GRP78 and its interaction with IRE-1α, including Cys420 site mutation.

Main Results:

• The CTH-H2S axis positively correlates with an anti-tumor TAM phenotype in BC.
• NaHS repolarized TAMs to M1 macrophages, inhibiting tumor-promoting activities.
• H2S-mediated S-sulfhydration of GRP78 at Cys420 enhanced IRE-1α phosphatase activity by inducing dissociation.

Conclusions:

• H2S-mediated GRP78 S-sulfhydration at Cys420 repolarizes TAMs via the IRE-1α pathway.
• This process reduces tumor burden and inhibits lung metastasis in BC.
• Targeting GRP78 S-sulfhydration offers a potential therapeutic strategy for TAM-M1 repolarization in breast cancer.