Large Oncosomes Induce Pro‐Metastatic Stromal‐Myeloid Reprogramming

Bone metastasis can be facilitated by systemic remodeling, yet the tumor‐derived signals that influence the bone marrow microenvironment remain incompletely understood. Large oncosomes (LOs) are atypically large (> 1 µm), tumor‐derived extracellular vesicles shed by amoeboid cancer cells. Here, we demonstrate that LOs function as systemic mediators of metastatic niche formation by activating innate immune sensing in bone marrow mesenchymal stem cells (BM‐MSCs). Systemic administration of 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)‐like phenotype. In vivo, genetic suppression of LO shedding in tumor cells reduced PMN‐MDSC accumulation in the bone marrow, which was reversed by systemic LO administration. Together, these findings support a model in which LO‐associated signals reprogram the bone marrow microenvironment to support metastatic colonization, identifying a previously unrecognized mechanism linking tumor vesiculation to immune remodeling at distant sites.