Mitochondria transfer via tunneling nanotubes drives macrophage immunosuppression and metabolic reprogramming in pediatric AML.

Although immunotherapy has revolutionized cancer treatment, its benefits in pediatric acute myeloid leukemia (AML) remain limited, partly due to an incomplete understanding of the AML microenvironment. While most studies focus on T cells, innate immune populations such as macrophages are less well explored. In pediatric AML patients, we demonstrate that immunosuppressive macrophages dominate the AML microenvironment and support growth of RUNX1::RUNX1T1 and KMT2A-rearranged leukemic blasts. In co-culture experiments, AML cells reprogrammed naïve and pro-inflammatory macrophages toward an anti-inflammatory state, characterized by suppression of NF-κB and other inflammatory pathways. This phenotypic switch requires direct cell contact and involves tunneling nanotube-mediated transfer of AML mitochondria to macrophages associated with metabolic rewiring toward oxidative phosphorylation. Functionally, these reprogrammed macrophages exhibited impaired phagocytosis, convey chemoresistance and reduced T cell- and bispecific antibody-mediated killing, facilitating immune escape. Our findings reveal a novel mechanism of immune suppression and suggest that targeting AML-macrophage interactions could enhance the efficacy of T cell-based immunotherapies.