Cancer Immunotherapy via Disruption of Integrin αvβ3 and CD47 Costabilization on Cancer Cell Surface

Abstract CD47/signal‐regulatory protein α (SIRPα) signaling enables malignant cells to evade macrophage‐mediated phagocytosis, offering a promising strategy for cancer therapy via immune checkpoint blockade. However, this strategy is widely debated due to several safety risks revealed by clinical studies, including anemia. Here, a CD47–SIRPα immune checkpoint treatment is investigated that mitigates anemic side effects by selectively interfering with the costabilization of CD47 and integrin αvβ3 on cancer cell surfaces, a phenomenon absent in erythrocytes. Multiplexed immunofluorescence analysis of 119 clinical breast cancer tissues reveals this costabilization. The engineered peptide PSFL‐NK13 effectively disrupts this costabilization, which enhances macrophage phagocytosis and delays tumor growth, without causing anemia or promoting angiogenesis. Thus, a stable interaction is identified between integrin αvβ3 and CD47 on the cancer cell membrane that facilitates immune evasion and demonstrates that targeting this interaction offers a safer therapeutic strategy for various tumors.