TGF-β-Enriched Exosomes from Acute Myeloid Leukemia Activate Smad2/3–MMP2 and ERK1/2 Signaling to Promote Leukemic Cell Proliferation, Migration, and Immune Modulation

Exosomes are extracellular vesicles secreted by all cell types, transporting nucleic acids, proteins, lipids, and metabolites. They are known to influence tumor biology by modulating cellular proliferation, invasion, and apoptosis. In acute myeloid leukemia (AML), the precise functions of exosomes remain incompletely characterized. Here, we present an integrated multi-omics study combining single-cell RNA sequencing (scRNA-seq) of bone marrow aspirates from AML patients and healthy donors with transcriptomic profiling of purified exosomes. This approach uniquely allowed us to link cellular transcriptional states with exosome content and function. We discovered a significant upregulation of exosome-related transcriptional activity in AML cells. Purified AML exosomes showed enhanced translational, transcriptional, and metabolic activity compared to those from healthy donors. Notably, these exosomes were highly enriched in transforming growth factor-β (TGF-β), a key regulator of tumor progression. Functional assays confirmed that AML-derived exosomes promote leukemic cell proliferation and migration. Mechanistically, these effects are mediated via activation of the Smad2/3–MMP2 and ERK1/2 signaling pathways. Furthermore, cell–cell interaction analysis revealed that AML exosomes reshape the bone marrow immune microenvironment by upregulating multiple immunoregulatory genes and pathways, revealing a novel immunomodulatory role. This study provides the first integrative demonstration that TGF-β–enriched exosomes actively drive AML progression through combined enhancement of leukemic aggressiveness and immune microenvironment remodeling. Our findings highlight exosomes and their signaling cascades as promising therapeutic targets, offering new avenues for innovative AML treatments.