由于基因组学和免疫学的快速发展，免疫治疗是肿瘤治疗的革命性治疗策略，免疫检查点抑制剂已成功地对包括造血系统恶性肿瘤在内的多种肿瘤类型取得缓解。然而，急性髓系白血病（AML）是一种异质性疾病，基于PD-1/PD-L1阻断的免疫治疗应用于AML仍缺乏系统论证。因此，迫切需要鉴定驱动肿瘤免疫抑制的分子并根据免疫检查点抑制剂的益处对患者进行分层。在这里，我们报道了 STAT5 在 AML 队列中高表达，并激活糖酵解基因的启动子以促进 AML 细胞中的糖酵解。因此，乳酸积累的增加促进了 E3BP 核转位并促进组蛋白乳酰化，最终诱导 PD-L1 转录。当与 STAT5 组成型激活的 AML 细胞共培养时，免疫检查点抑制剂可以阻断微环境中 PD-1/PD-L1 和反应性 CD8 T 细胞的相互作用。临床上，初诊AML患者骨髓中乳酸积累与STAT5以及PD-L1表达呈正相关。因此，我们阐明了 AML 进展中的 STAT5-乳酸-PD-L1 网络，这表明 STAT5 诱导旺盛的糖酵解和乳酸积累的 AML 患者可能受益于基于 PD-1/PD-L-1 的免疫治疗。© 2023.四川大学华西医院。

Immunotherapy is a revolutionized therapeutic strategy for tumor treatment attributing to the rapid development of genomics and immunology, and immune checkpoint inhibitors have successfully achieved responses in numbers of tumor types, including hematopoietic malignancy. However, acute myeloid leukemia (AML) is a heterogeneous disease and there is still a lack of systematic demonstration to apply immunotherapy in AML based on PD-1/PD-L1 blockage. Thus, the identification of molecules that drive tumor immunosuppression and stratify patients according to the benefit from immune checkpoint inhibitors is urgently needed. Here, we reported that STAT5 was highly expressed in the AML cohort and activated the promoter of glycolytic genes to promote glycolysis in AML cells. As a result, the increased-lactate accumulation promoted E3BP nuclear translocation and facilitated histone lactylation, ultimately inducing PD-L1 transcription. Immune checkpoint inhibitor could block the interaction of PD-1/PD-L1 and reactive CD8+ T cells in the microenvironment when co-culture with STAT5 constitutively activated AML cells. Clinically, lactate accumulation in bone marrow was positively correlated with STAT5 as well as PD-L1 expression in newly diagnosed AML patients. Therefore, we have illustrated a STAT5-lactate-PD-L1 network in AML progression, which demonstrates that AML patients with STAT5 induced-exuberant glycolysis and lactate accumulation may be benefited from PD-1/PD-L-1-based immunotherapy.© 2023. West China Hospital, Sichuan University.