Caveolin-1 drives vasculogenic mimicry in lung adenocarcinoma through autophagy-mediated glycolytic reprogramming

Lung adenocarcinoma (LUAD) remains a leading cause of cancer-related mortality, characterized by limited therapeutic options and poor prognosis. Caveolin-1 (Cav-1), a key structural protein of caveolae, has been implicated in multiple oncogenic processes, including metastasis. However, its role in LUAD, particularly in regulating vasculogenic mimicry (VM), remains poorly characterized. In this study, we discovered that higher Cav-1 expression is associated with a poor prognosis and promotes tumor cell proliferation, migration, and invasion. Mechanistically, Cav-1 potentiates autophagic activity, which induces glycolytic reprogramming to support the formation of VM channels. This process was validated by the upregulation of VM-related proteins (VE-Cadherin, MMP2) and was effectively suppressed by inhibiting either autophagy or glycolysis. Single-cell sequencing and spatial transcriptomics analysis further elucidated the impact of Cav-1 on the LUAD tumor microenvironment. Our study unveils Cav-1-autophagy-glycolysis-VM axis essential for LUAD progression, proposing that combined targeting of autophagy (CQ) and glycolysis (2-DG) could disrupt tumor VM and overcome therapeutic resistance.