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

scRNA-seq describes the immunomodulatory effect of sorafenib maintenance post-transplant. • Sorafenib promotes NK cell IFN-γ production via macrophage-NK cell immune crosstalk. • Sorafenib promotes IL-18 production and release via inhibiting mitochondrial respiration. SUMMARY Sorafenib maintenance post-transplantation reduces relapse via inducing graft-versus-leukemia (GVL) effect in 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. Download: Download high-res image (194KB) Download: Download full-size image