Endothelial PDLIM5 promotes tip cell filopodia formation and tumor angiogenesis by regulating ACTN1/ACTN4-dependent...

Filopodia formation by tumor endothelial cells (TECs) is critical for tip cell-guided sprouting angiogenesis and tumor growth. However, the cytoskeletal organization that underlies this process remains elusive. Here, we demonstrates that TECs highly express actin-binding genes, with PDZ and LIM domain 5 (PDLIM5), a cytoskeletal protein, significantly upregulated in TECs and correlated with poor patient survival. Endothelial-specific deletion of Pdlim5 inhibits sprouting angiogenesis by disrupting filopodia formation through its interaction with actinin-1/actinin-4 (ACTN1/ACTN4) via its S593/F596 residues, promoting filamentous actin (F-actin) bundling. Pdlim5 knockout not only reduces tumor growth but also normalizes tumor vasculature, alleviates hypoxia, and enhances immunotherapy and chemotherapy responses. These findings highlight the PDLIM5's role in facilitating tumor angiogenesis via ACTN1/ACTN4-mediated F-actin bundling and tip cell filopodia formation, providing mechanistic insights that may inform future therapeutic strategies targeting this pathway.