| Cancer stem cells are critical for cancer progression and chemoresistance. Although the metabolic programming for the maintenance of stem cells has been studied, how metabolism regulates cancer stem cells (CSCs) and chemoresistance remains elusive. Here, we demonstrate that JAK/STAT3 regulates lipid metabolism, which promotes breast CSCs (BCSCs) and chemoresistance. Inhibiting JAK/STAT3 blocks BCSC self-renewal and expression of diverse lipid metabolic genes, including carnitine palmitoyltransferase 1B (CPT1B), which encodes the critical enzyme for fatty acid beta-oxidation (FAO). Moreover, mammary adipocyte-derived leptin upregulates STAT3 activity and CPT1B expression in BCSCs. Human breast cancer-derived data suggest STAT3-CPT1B-FAO pathway promotes cancer cell stemness and chemoresistance. Blocking this pathway re-sensitizes them to chemotherapy. This study identifies FAO as a distinct metabolic feature of breast CSCs, supporting STAT3 and FAO as metabolic targets to reduce CSCs and reverse breast cancer chemoresistance. |
