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. This evidence concerns the gene HSPA5 and breast cancer.