Targeting phagocytosis checkpoints for cancer immunotherapy

The ability of macrophages to eliminate cancer cells through phagocytosis is tightly controlled by pro-phagocytic and inhibitory phagocytic receptors. Pro-phagocytic receptors such as Fc receptors, macrophage-1 antigen (MAC-1; also known as CD11b/CD18) and signalling lymphocytic activation molecule family member 7 (SLAMF7) have been shown to facilitate tumour cell elimination in pre-clinical models, and Fc receptors have been determined critical for the anti-tumour efficacy of several monoclonal antibodies in the clinic. Pre-clinical and early clinical studies have also highlighted that blocking of inhibitory phagocytic checkpoints, most prominently signal-regulatory protein α (SIRPα) and its ligand CD47, is a promising therapeutic approach for cancer. However, concerns about limited efficacy and toxicities in recent clinical trials have led to diminished enthusiasm for this approach. In this Review, we examine the evidence supporting phagocytic checkpoints as targets for cancer therapy, while highlighting current challenges associated with this therapeutic strategy. We also offer recommendations for enhancing the efficacy and safety of this approach in future work.