L-Arginine Reinforces NK Cell-Mediated GVL Effect in Bone Marrow of AML Patients with Early Relapse Post-Allo-HSCT

Relapse is a leading cause of death after allogeneic hematopoietic stem cell transplantation (allo-HSCT) for acute myeloid leukemia (AML). However, the underlying mechanisms remain poorly understood. Natural killer (NK) cells play a crucial role in tumor surveillance and cancer immunotherapy, and NK cell dysfunction has been observed in various tumors. Here, we performed ex vivo experiments to systematically characterize the mechanisms underlying the dysfunction of bone marrow-derived NK (BMNK) cells isolated from AML patients experiencing early relapse after allo-HSCT. Using high-resolution mass spectrometry, we demonstrated that the level of L-arginine decreased in the bone marrow and was associated with BMNK cell paucity and dysfunction in these AML patients. In addition, highly expressed arginase-1 in M2 macrophages induced L-arginine deficiency in the bone marrow microenvironment and suppressed mitochondrial oxidative phosphorylation and cytotoxicity of BMNK cells. Additionally, L-arginine deficiency triggered the formation of TFEB-containing transcriptional condensates, and induced liquid-liquid phase separation of TFEB, which resulted in abnormal autophagy and apoptosis of BMNK cells. Furthermore, the supplementation with L-arginine restored NK cell-mediated anti-leukemic responses in the leukemia xenograft mouse model and patient-derived xenografted (PDX) model. Thus, our study reveals a mechanism through which L-arginine deficiency compromises NK cells, highlighting the potential of L-arginine supplementation to improve NK cell-based cancer treatments.