SIRPα–CD47 Immune Checkpoint Blockade in Anticancer Therapy

Inhibitory immune checkpoint blockade has been one of the most significant advances in anticancer therapy of the past decade. Research so far has largely focused on improving adaptive immune functions, but recent studies have indicated that the signal-regulatory protein (SIRP)α–CD47 pathway, a phagocytosis checkpoint in macrophages and other innate immune cells, may be an interesting therapeutic target. Here, we summarize current knowledge about SIRPα–CD47 blockade, and highlight key issues for future investigations. These include the targeting of prophagocytic receptors (Fc receptors or otherwise) to complement SIRPα–CD47 blockade, the understanding of constraints on phagocytosis other than the SIRPα–CD47 checkpoint and the contribution of immune cells other than macrophages. A better understanding of how SIRPα–CD47 blockade works may aid in identifying patients suitable for this therapy, avoiding potential toxicities and designing optimal combination therapies. Blockade of the SIRPα–CD47 innate immune checkpoint shows promise as a new way to treat cancer. Accumulating data suggest that SIRPα–CD47 blockade per se may not be sufficient to trigger phagocytosis of tumor cells. Engagement of prophagocytic receptors such as Fc receptors or SLAMF7 is also needed. The impact of SIRPα–CD47 blockade may be further improved by relieving additional constraints on phagocytosis.