Rewiring cancer cell fate toward vasculogenic mimicry: from classical to unconventional processes

Pathological vasculogenic mimicry (VM) is the process by which aggressive tumor stem cells form perfusable, matrix-rich, vessel-like networks, facilitating tumor perfusion and metastasis. Several well-characterized VM drivers include hypoxia, acidity, growth factors, and inflammatory molecules. Likewise, canonical and non-canonical transitions, such as epithelial-to-mesenchymal, epithelial-to-endothelial, endothelial-to-mesenchymal, and epithelial-mesenchymal plasticity contribute to VM formation. In addition, atypical mechanisms such as cell-cell fusion, polyploidization, gene silencing, and processes associated with viral infections have also been linked to VM induction. Clinically, VM has been associated with poor prognosis, metastasis, and resistance to antiangiogenic, chemo- and radiotherapeutic compounds, which may independently trigger or exacerbate VM. Therapeutic strategies to fight this highly adaptive process include combination regimens that simultaneously inhibit angiogenesis and VM, thereby preventing the emergence of alternative survival mechanisms. Likewise, key nodes and signaling pathways involved in VM, such as Notch, Wnt, and PI3K/AKT, are under active preclinical evaluation, together with pro-differentiating factors that attenuate stem-associated traits. However, despite its therapeutic relevance, the mechanistic basis of VM remains insufficiently integrated, leaving a gap in biomedical literature. To address this, the aim of this review was to provide comprehensive coverage of current evidence encompassing both well-established processes associated with VM and those not yet fully characterized. Our work integrates the analysis of signaling pathways, key molecular players, lineage plasticity, and microenvironmental factors that orchestrate VM. In addition, therapeutic challenges and opportunities are also discussed.