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Tumor\u2010associated 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\u2010sulfhydration in TAM reprogramming in breast cancer (BC). Therefore, the aim is to investigate whether protein S\u2010sulfhydration can regulate TAM reprogramming and its underlying mechanism in BC. The results showed that in BC, the CTH\u2010H<jats:sub>2<\/jats:sub>S axis is positively correlated with the presence of an anti\u2010tumor phenotype in TAMs. NaHS, as an H<jats:sub>2<\/jats:sub>S donor, repolarized TAMs into M1 macrophages to block the tumor\u2010promoting activities of TAMs both in vitro and in vivo. Mechanistically, H<jats:sub>2<\/jats:sub>S\u2010mediated S\u2010sulfhydration of the protein chaperone glucose\u2010regulated\u2010protein 78 (GRP78) induced endoplasmic reticulum transmembrane protein kinase\u20101\u03b1 (IRE\u20101\u03b1) dissociation from GRP78, which enhanced the phosphatase activity of IRE\u20101\u03b1 itself in BC\u2010TAMs, while the Cys420 site mutation of GRP78 interfered with these effects. Collectively, GRP78 S\u2010sulfhydrylation mediated by H<jats:sub>2<\/jats:sub>S at the Cys420 residue decreased the tumor burden and inhibited lung metastasis of BC through reprograming TAMs via activating the IRE\u20101\u03b1 pathway, indicating that targeting GRP78 S\u2010sulfhydration represents a promising intervention for TAM\u2010M1 repolarization in BC.<\/jats:p>","DOI":"10.1002\/advs.202413607","type":"journal-article","created":{"date-parts":[[2025,1,5]],"date-time":"2025-01-05T00:07:49Z","timestamp":1736035669000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Hydrogen Sulfide Promotes TAM\u2010M1 Polarization through Activating IRE\u20101\u03b1 Pathway via GRP78 S\u2010Sulfhydrylation to against Breast Cancer"],"prefix":"10.1002","volume":"12","author":[{"given":"Mingyi","family":"Ju","sequence":"first","affiliation":[{"name":"Department of Pharmacology School of Pharmacy China Medical University  Shenyang 110122 China"},{"name":"Liaoning Key Laboratory of molecular targeted anti\u2010tumor drug development and evaluation China Medical University  Shenyang 110122 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weiwei","family":"Tong","sequence":"additional","affiliation":[{"name":"Department of Pharmacology School of Pharmacy China Medical University  Shenyang 110122 China"},{"name":"Liaoning Key Laboratory of molecular targeted anti\u2010tumor drug development and evaluation China Medical University  Shenyang 110122 China"},{"name":"Department of Laboratory Medicine Shengjing Hospital of China Medical University  Shenyang 110122 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jia","family":"Bi","sequence":"additional","affiliation":[{"name":"Department of Pharmacology School of Pharmacy China Medical University  Shenyang 110122 China"},{"name":"Liaoning Key Laboratory of molecular targeted anti\u2010tumor drug development and evaluation China Medical University  Shenyang 110122 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xianxin","family":"Zeng","sequence":"additional","affiliation":[{"name":"Department of Pharmacology School of Pharmacy China Medical University  Shenyang 110122 China"},{"name":"Liaoning Key Laboratory of molecular targeted anti\u2010tumor drug development and evaluation China Medical University  Shenyang 110122 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aoshuang","family":"Qi","sequence":"additional","affiliation":[{"name":"Department of Pharmacology School of Pharmacy China Medical University  Shenyang 110122 China"},{"name":"Liaoning Key Laboratory of molecular targeted anti\u2010tumor drug development and evaluation China Medical University  Shenyang 110122 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingli","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Pharmacology School of Pharmacy China Medical University  Shenyang 110122 China"},{"name":"Liaoning Key Laboratory of molecular targeted anti\u2010tumor drug development and evaluation China Medical University  Shenyang 110122 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"Wen","sequence":"additional","affiliation":[{"name":"Department of Pharmacology School of Pharmacy China Medical University  Shenyang 110122 China"},{"name":"Liaoning Key Laboratory of molecular targeted anti\u2010tumor drug development and evaluation China Medical University  Shenyang 110122 China"},{"name":"Department of Breast Surgery The Fourth Affiliated Hospital of China Medical University  Shenyang 110122 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9264-6455","authenticated-orcid":false,"given":"Lin","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Pharmacology School of Pharmacy China Medical University  Shenyang 110122 China"},{"name":"Liaoning Key Laboratory of molecular targeted anti\u2010tumor drug development and evaluation China Medical University  Shenyang 110122 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0404-7098","authenticated-orcid":false,"given":"Minjie","family":"Wei","sequence":"additional","affiliation":[{"name":"Department of Pharmacology School of Pharmacy China Medical University  Shenyang 110122 China"},{"name":"Liaoning Key Laboratory of molecular targeted anti\u2010tumor drug development and evaluation China Medical University  Shenyang 110122 China"},{"name":"School of Pharmacy Qiqihar Medical University  Qiqihar 161006 China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,1,4]]},"reference":[{"key":"e_1_2_9_1_1","first-page":"1081","volume":"52","author":"Han Z.\u2010J.","year":"2018","journal-title":"Int. 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