Endocrine therapy is the standard treatment for estrogen receptor (ER)-positive 
breast cancer, but tumors eventually develop resistance. However, endocrine 
therapy resistance mechanisms mediated through interactions between breast 
cancer cells and tumor-associated macrophages (TAMs) are still unclear. Here, we 
characterized sodium/glucose cotransporter 1 (SGLT1) overexpression drives the 
highly glycolytic phenotype of tamoxifen-resistant breast cancer cells where 
enhanced lactic acid secretion promotes M2-like TAM polarization via the 
hypoxia-inducible factor-1α/signal transducer and activator of transcription-3 
pathway. In turn, M2-like TAMs activate breast cancer cells through 
EGFR/PI3K/Akt signaling, providing feedback to upregulate SGLT1 and promote 
tamoxifen resistance and accelerate tumor growth in vitro and in vivo. Higher 
expression of SGLT1 and CD163+ TAMs was associated with endocrine-resistant 
ER-positive breast cancers. Our study identifies a novel vicious cycle of 
metabolic reprogramming, M2-like TAM polarization, and endocrine therapy 
resistance, which involves SGLT1, proposing SGLT1 as a therapeutic target to 
overcome endocrine therapy resistance in breast cancer.