癌细胞通常过度表达 CD47，从而触发巨噬细胞上表达的抑制性受体 SIRPα，以逃避吞噬作用和抗肿瘤免疫。 CD47 或 SIRPα 的药物阻断显示出作为抗癌治疗的前景，尽管 CD47 阻断与血液学毒性有关，这可能反映了其在正常细胞上的广泛表达模式。在这里，我们发现，除了触发 SIRPα 之外，CD47 还通过 SIRPα 独立机制抑制吞噬作用。由于 CD47 和 SLAMF7 之间的顺式相互作用，这种机制阻止了肿瘤细胞上促吞噬配体 SLAMF7 引发的吞噬作用。 CD47-SLAMF7 相互作用被 CD47 阻断和一流的激动剂 SLAMF7 抗体破坏，但不被 SIRPα 阻断破坏，从而促进抗肿瘤免疫。因此，CD47 不仅通过与 SIRPα 结合来抑制吞噬作用，还通过屏蔽肿瘤细胞上的细胞固有的促吞噬配体来抑制吞噬作用，对这一机制的了解可能会影响出于治疗目的在 CD47 阻断或 SIRPα 阻断之间做出决定。© 2023。作者（ s)，获得 Springer Nature America, Inc. 的独家许可。

Cancer cells often overexpress CD47, which triggers the inhibitory receptor SIRPα expressed on macrophages, to elude phagocytosis and antitumor immunity. Pharmacological blockade of CD47 or SIRPα is showing promise as anticancer therapy, although CD47 blockade has been associated with hematological toxicities that may reflect its broad expression pattern on normal cells. Here we found that, in addition to triggering SIRPα, CD47 suppressed phagocytosis by a SIRPα-independent mechanism. This mechanism prevented phagocytosis initiated by the pro-phagocytic ligand, SLAMF7, on tumor cells, due to a cis interaction between CD47 and SLAMF7. The CD47-SLAMF7 interaction was disrupted by CD47 blockade and by a first-in-class agonist SLAMF7 antibody, but not by SIRPα blockade, thereby promoting antitumor immunity. Hence, CD47 suppresses phagocytosis not only by engaging SIRPα, but also by masking cell-intrinsic pro-phagocytic ligands on tumor cells and knowledge of this mechanism may influence the decision between CD47 blockade or SIRPα blockade for therapeutic purposes.© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.