The FOXC2‐LAMA4 Axis Orchestrates Vasculogenic Mimicry and Immunosuppressive Niche Formation to Drive Metastatic Cascade in Renal Cell Carcinoma

ABSTRACT The aggressive metastatic propensity of advanced clear cell renal cell carcinoma (ccRCC) originates from intratumoral heterogeneity. Through integrated single‐cell and spatial multi‐omics profiling, we identified a FOXC2 + tumor subpopulation endowed with vasculogenic mimicry capability as pivotal effector cells driving metastasis. Mechanistically, the transcription factor FOXC2 binds the promoter region of LAMA4 to activate its expression, initiating metastatic cascades via vasculogenic mimicry remodeling. In orthotopic lung metastasis models, FOXC2 + tumor cells leveraged LAMA4 to reshape the pulmonary metastatic niche, thereby reinforcing distant metastatic dissemination. Tumor‐secreted LAMA4 engaged macrophage surface receptor ITGA6 to trigger GATA3 activation and reprogram macrophages toward a pro‐metastatic and immunosuppressive phenotype. Disruption of LAMA4‐ITGA6 binding substantially attenuated FOXC2‐LAMA4‐mediated metastatic burden. These results reveal a novel mechanism by which FOXC2 + tumor cells promote metastasis in advanced ccRCC and further establish the therapeutic potential of targeting FOXC2‐LAMA4 in blocking the metastatic cascade of ccRCC.