A novel peptide blocking CD93/IGFBP7 interaction normalizes tumor vessels and synergizes with radiotherapy for cancer immunotherapy

The aberrant tumor vasculature fosters a permissive microenvironment that impedes immune effector cell infiltration and simultaneously promotes neoplastic progression. CD93 is an important target for antiangiogenic normalization therapy. Here, we found that the expression of CD93 and its ligand IGFBP7 were significantly upregulated in cancers and closely associated with various pro-angiogenic factors. Next, we identified the CD93 binding peptides (CBP). After systematic D-amino acid modification and retro-inversion, CBP-D8 peptide exhibited the highest blocking activity on CD93/IGFBP7 interaction, and potent inhibition on the migration of endothelial cells. Besides, CBP-D8 peptide significantly facilitated cytotoxic CD8 + T cells and NK cells infiltration through enhanced blood perfusion and increased coverage of pericytes and vascular smooth muscle cells. More importantly, CBP-D8 peptide combined with radiotherapy significantly abrogated tumor growth and elicited systemic antitumor immune response. Our study identified a novel peptide blocking CD93/IGFBP7 interaction to normalize tumor vascular function, as well as revealed an approach to promote a favorable tumor microenvironment for the therapeutic intervention. The schematic overview of the combined therapy with CD93-targeting peptide CBP-D8 and radiotherapy to promote tumor vascular normalization and cancer immunotherapy.