Leukaemia stem cells (LSCs) in acute myeloid leukaemia present a considerable treatment challenge due to their resistance to chemotherapy and immunosurveillance. The connection between these properties in LSCs remains poorly understood. Here we demonstrate that inhibition of tyrosine phosphatase SHP-1 in LSCs increases their glycolysis and oxidative phosphorylation, enhancing their sensitivity to chemotherapy and vulnerability to immunosurveillance. Mechanistically, SHP-1 inhibition leads to the upregulation of phosphofructokinase platelet (PFKP) through the AKT–β-catenin pathway. The increase in PFKP elevates energy metabolic activities and, as a consequence, enhances the sensitivity of LSCs to chemotherapeutic agents. Moreover, the upregulation of PFKP promotes MYC degradation and, consequently, reduces the immune evasion abilities of LSCs. Overall, our study demonstrates that targeting SHP-1 disrupts the metabolic balance in LSCs, thereby increasing their vulnerability to chemotherapy and immunosurveillance. This approach offers a promising strategy to overcome LSC resistance in acute myeloid leukaemia.

急性髓系白血病中的白血病干细胞（LSC）由于其对化疗和免疫监视的抵抗力而提出了相当大的治疗挑战。 LSC 中这些特性之间的联系仍然知之甚少。在这里，我们证明抑制 LSC 中的酪氨酸磷酸酶 SHP-1 会增加其糖酵解和氧化磷酸化，从而增强其对化疗的敏感性和对免疫监视的脆弱性。从机制上讲，SHP-1 抑制通过 AKT-β-连环蛋白途径导致磷酸果糖激酶血小板 (PFKP) 上调。 PFKP 的增加提高了能量代谢活动，从而增强了 LSC 对化疗药物的敏感性。此外，PFKP 的上调促进 MYC 降解，从而降低 LSC 的免疫逃避能力。总的来说，我们的研究表明，靶向 SHP-1 会破坏 LSC 的代谢平衡，从而增加它们对化疗和免疫监视的脆弱性。这种方法为克服急性髓系白血病的 LSC 耐药性提供了一种有前景的策略。