Fat mass and obesity-associated protein (FTO), an RNA N⁶-methyladenosine (m⁶A) demethylase, plays oncogenic roles in various cancers, presenting an opportunity for the development of effective targeted therapeutics. Here, we report two potent small-molecule FTO inhibitors that exhibit strong anti-tumor effects in multiple types of cancers. We show that genetic depletion and pharmacological inhibition of FTO dramatically attenuate leukemia stem/initiating cell self-renewal and reprogram immune response by suppressing expression of immune checkpoint genes, especially LILRB4. FTO inhibition sensitizes leukemia cells to T cell cytotoxicity and overcomes hypomethylating agent-induced immune evasion. Our study demonstrates that FTO plays critical roles in cancer stem cell self-renewal and immune evasion and highlights the broad potential of targeting FTO for cancer therapy.

脂肪量和肥胖相关蛋白 (FTO) 是一种 RNA N ⁶ -甲基腺苷 (m ⁶ A) 去甲基化酶，在各种癌症中发挥致癌作用，为开发有效的靶向治疗提供了机会。在这里，我们报告了两种有效的小分子 FTO 抑制剂，它们在多种类型的癌症中表现出强大的抗肿瘤作用。我们表明，FTO 的基因缺失和药理学抑制通过抑制免疫检查点基因，尤其是LILRB4的表达，显着减弱白血病干细胞/启动细胞自我更新和重新编程免疫反应。. FTO 抑制使白血病细胞对 T 细胞细胞毒性敏感并克服低甲基化剂诱导的免疫逃避。我们的研究表明，FTO 在癌症干细胞自我更新和免疫逃避中发挥着关键作用，并突出了靶向 FTO 用于癌症治疗的广泛潜力。