AbstractBackgroundCD47 is a widely expressed transmembrane protein located on the surface of somatic cells. It mediates a variety of cellular processes including apoptosis, proliferation, adhesion, and migration. An important role for CD47 is the transmission of a “Don't eat me” signal by interacting with SIRPα on the macrophage surface membrane, thereby preventing the phagocytosis of normal cells. However, cancer cells can take advantage of this autogenous signal to protect themselves from phagocytosis, thus enabling immune escape. Blocking the interaction between CD47 and SIRPα has proven to be effective in removing cancer cells. The treatment of various cancers with CD47 monoclonal antibodies has also been validated.MethodsWe designed and synthesized a peptide (RS17), which can specifically bind to CD47 and block CD47‐SIRPα signaling. The affinity of RS17 for CD47‐expressing tumor cells was determined, while the inhibition of CD47‐SIRPα signaling was evaluated in vitro and in vivo.ResultsThe results indicated that RS17 significantly promotes the phagocytosis of tumor cells by macrophages and had a similar therapeutic effect compared with a positive control (CD47 monoclonal antibodies). In addition, a cancer xenograft mouse model was established using CD47‐expressing HepG2 cells to evaluate the effect of RS17 on tumor growth in vivo. Using ex vivo and in vivo mouse models, RS17 demonstrated a high inhibitory effect on tumor growth.ConclusionsBased on our results, RS17 may represent a novel therapeutic peptide for cancer therapy.