Large oncosomes reprogram bone marrow mesenchymal stem cells to establish a pre-metastatic niche

Metastatic progression depends on the systemic remodeling of distant tissues before tumor cell arrival, yet the cancer-derived signals that orchestrate this process remain poorly understood. Large oncosomes (LOs) are atypically large (>1 um), tumor-derived extracellular vesicles shed by invasive cancer cells. Here, we demonstrate that LOs function as systemic mediators of pre-metastatic niche formation by activating innate immune sensing in bone marrow mesenchymal stem cells (BM-MSCs). Systemic administration of prostate- and breast cancer-derived LOs to immunocompetent tumor-bearing mice did not affect primary tumor growth but increased metastatic burden. LOs induced a robust, dose-dependent interferon-driven inflammatory program, characterized by interferon-stimulated genes and neutrophil chemokines. Mechanistically, this response was driven by LO-associated nucleic acids activating convergent cytosolic DNA- and RNA-sensing pathways in recipient stromal cells. LO-conditioned BM-MSCs promoted the accumulation and polarization of neutrophils toward an immunosuppressive, polymorphonuclear myeloid-derived suppressor cell (PMN-MDSC) phenotype. In vivo, genetic suppression of LO shedding in tumor cells reduced PMN-MDSC accumulation in the bone marrow, which was reverted by systemic LO administration. Together, these findings establish LOs as specialized carriers of immunomodulatory signals that reprogram the bone marrow microenvironment to support metastatic colonization, identifying a previously unrecognized mechanism linking tumor vesiculation to immune remodeling at distant sites.