Medium-sized macrocyclic peptides are an alternative to small compounds and large biomolecules as a class of pharmaceutics. The CD47-SIRPα signaling axis functions as an innate immune checkpoint that inhibits phagocytosis in phagocytes and has been implicated as a promising target for cancer immunotherapy. The potential of macrocyclic peptides that target this signaling axis as immunotherapeutic agents has remained unknown, however. Here we have developed a macrocyclic peptide consisting of 15 amino acids that binds to the ectodomain of mouse SIRPα and efficiently blocks its interaction with CD47 in an allosteric manner. The peptide markedly promoted the phagocytosis of antibody-opsonized tumor cells by macrophages in vitro as well as enhanced the inhibitory effect of anti-CD20 or anti-gp75 antibodies on tumor formation or metastasis in vivo. Our results suggest that allosteric inhibition of the CD47-SIRPα interaction by macrocyclic peptides is a potential approach to cancer immunotherapy.

中型大环肽可替代小化合物和大生物分子作为一类药物。CD47-SIRPα信号轴起抑制吞噬细胞吞噬作用的先天免疫检查点的作用，并被认为是癌症免疫疗法的有希望的靶点。然而，靶向该信号轴作为免疫治疗剂的大环肽的潜力仍然未知。在这里，我们开发了一种由15个氨基酸组成的大环肽，该大环肽与小鼠SIRPα的胞外域结合，并以变构方式有效阻断其与CD47的相互作用。该肽在体外可显着促进巨噬细胞对抗体调理的肿瘤细胞的吞噬作用以及增强抗CD20或抗gp75抗体对体内肿瘤形成或转移的抑制作用。我们的结果表明，大环肽对CD47-SIRPα相互作用的变构抑制是癌症免疫治疗的一种潜在方法。