Mechanistic insights into the role of hypoxia-preconditioned mesenchymal stem cell-derived small extracellular vesicles in angiogenesis, adhesion, emt, and tumor progression in solid tumors

Solid tumors harbor a highly hypoxic tumor microenvironment (TME) that plays a pivotal role in tumor progression, therapeutic resistance, and metastasis. Mesenchymal stem/stromal cells (MSCs) are actively recruited into these hypoxic regions, where they undergo phenotypic reprogramming into tumor-associated MSCs (TA-MSCs). Under hypoxic conditions, MSCs secrete small extracellular vesicles (sEVs) with altered molecular cargo, particularly enriched in selected hypoxia-responsive miRNAs, including miR-21-5p, miR-210-3p, miR-193a-3p, and miR-5100. Other hypoxia-associated mediators, including proteins such as HMGB1 and TGF-β, have also been implicated in MSC-mediated signaling; however, their specific association with hypoxia-conditioned MSC-derived sEV (Hypo-MSC-sEV) cargo remains incompletely established and may involve vesicle-associated, soluble, or recipient cell-induced mechanisms depending on the experimental context. This review provides a comprehensive overview of the mechanistic contributions of Hypo-MSC-sEVs to solid tumor progression. Current evidence suggests that Hypo-MSC-sEVs act as important mediators of intercellular communication by transmitting hypoxia-adapted signals from poorly oxygenated tumor regions to neighboring normoxic tumor cells and, potentially, to distant tissues. Available evidence indicates that Hypo-MSC-sEVs may promote tumor angiogenesis through VEGF-related signaling together with Notch-, JNK/HIF-1α-, and selected miRNA-dependent mechanisms. They may also contribute to tumor cell adhesion remodeling by modulating integrin- and cadherin-associated signaling pathways, thereby reinforcing downstream FAK–Src and PI3K/AKT signaling. These signaling events may facilitate epithelial–mesenchymal transition (EMT)-associated plasticity through activation of key transcription factors, including Snail, Slug, Twist, and ZEB1/2. Furthermore, Hypo-MSC-sEVs may reinforce cytoskeletal remodeling, extracellular matrix (ECM) remodeling, migratory capacity, and metastatic dissemination. However, several proposed mechanisms—particularly those related to organ-specific pre-metastatic niche formation, proteolytic remodeling, and organotropic signaling—remain supported primarily by tumor-derived sEV studies rather than direct evidence from Hypo-MSC-sEV models. Current evidence also indicates that Hypo-MSC-sEVs can modulate the tumor immune microenvironment, most consistently through macrophage polarization, whereas their contribution to immune checkpoint-associated pathways and other immunosuppressive mechanisms remains less completely defined. In addition, the relative contribution of vesicle-associated cargo, soluble secreted factors, and recipient cell-induced signaling requires further clarification. By synthesizing evidence from in vitro, in vivo, and emerging clinical studies, this review highlights the multifaceted role of the Hypo–MSC–sEV axis in orchestrating multiple hallmarks of cancer while emphasizing current evidence gaps and priorities for future investigation. Collectively, current evidence suggests that targeting the Hypo–MSC–sEV axis may provide new opportunities for the development of therapeutic strategies and minimally invasive biomarkers for hypoxic solid tumors.