Hydrogen sulfide (H2S)-mediated protein S-sulfhydration has been shown to play critical roles in several diseases. Tumor-associated macrophages (TAMs) are the predominant population of immune cells present within solid tumor tissues, and they function to restrict antitumor immunity. However, no previous study has investigated the role of protein S-sulfhydration in TAM reprogramming in breast cancer (BC). Therefore, the aim is to investigate whether protein S-sulfhydration can regulate TAM reprogramming and its underlying mechanism in BC. The results showed that in BC, the CTH-H2S axis is positively correlated with the presence of an anti-tumor phenotype in TAMs. NaHS, as an H2S donor, repolarized TAMs into M1 macrophages to block the tumor-promoting activities of TAMs both in vitro and in vivo. Mechanistically, H2S-mediated S-sulfhydration of the protein chaperone glucose-regulated-protein 78 (GRP78) induced endoplasmic reticulum transmembrane protein kinase-1α (IRE-1α) dissociation from GRP78, which enhanced the phosphatase activity of IRE-1α itself in BC-TAMs, while the Cys420 site mutation of GRP78 interfered with these effects. Collectively, GRP78 S-sulfhydrylation mediated by H2S at the Cys420 residue decreased the tumor burden and inhibited lung metastasis of BC through reprograming TAMs via activating the IRE-1α pathway, indicating that targeting GRP78 S-sulfhydration represents a promising intervention for TAM-M1 repolarization in BC.
Keywords: S‐sulfhydrylation; breast cancer; hydrogen sulfide; macrophage repolarization; tumor‐associated macrophages.
© 2025 The Author(s). Advanced Science published by Wiley‐VCH GmbH.