Sorafenib enhances graft-versus-leukemia activity through IL-18-mediated macrophage and NK cell crosstalk in FLT3-ITD acute myeloid leukemia.

Sorafenib maintenance post-transplantation reduces relapse via inducing graft-versus-leukemia (GVL) effect in FMS-like tyrosine kinase 3 (FLT3)-internal tandem duplication (ITD) + acute myeloid leukemia (AML) undergoing allogenic hematopoietic stem cell transplantation (allo-HSCT), but the mechanism remains unclear. In this study, we investigated the effect of sorafenib in bone marrow immune microenvironment using single-cell RNA sequencing (scRNA-seq) and explored the mechanisms. We found that sorafenib promoted the macrophage-natural killer (NK) cell crosstalk through interleukin (IL)-18, elevating NK cell cytotoxicity and GVL effect. Mechanistically, sorafenib inhibited the mitochondrial electron transport complex I and V, resulting in metabolic reprogramming, thereby promoting IL-18 production via increasing PKM2-RelA binding and IL-18 release via triggering caspase-3/GSDME-dependent pyroptosis in macrophages. Our findings unveil the mechanism by which sorafenib enhances GVL in the FLT3-ITD+ AML patients undergoing allo-HSCT, providing theoretical and practical basis for constructing new strategies to prevent relapse post-transplantation.