Targeting inhibitory phagocytosis checkpoints in cancer immunotherapy: mechanisms, therapeutic strategies, and translational challenges

Abstract

Tumors evade macrophage-mediated clearance through mechanistically distinct but functionally convergent anti-phagocytic pathways. This review examines canonical and emerging receptor–ligand “don’t eat me” axes, Siglec-dependent glyco-inhibitory checkpoints, and an emerging noncanonical glycocalyx barrier associated with sialylated CD43, linking these mechanisms to impaired macrophage recognition and activation, phagocytic synapse formation, and target-cell engulfment. We discuss their molecular basis, roles in tumor immune evasion, and therapeutic targeting, with emphasis on checkpoint-blocking antibodies, Fc-engineered antibodies, bispecific molecules, fusion proteins, and glyco-immune interventions. Clinical translation has nevertheless been uneven because of on-target/off-tumor toxicity, insufficient tumor selectivity, insufficient pro-phagocytic signaling, macrophage heterogeneity, and parallel immunosuppressive pathways. The strength and maturity of the supporting evidence vary considerably across targets, with CD47–SIRPα remaining the most extensively studied and clinically developed axis. Further progress will require mechanism- and evidence-guided target prioritization, biomarker-informed patient selection, and drug engineering to improve therapeutic selectivity and therapeutic windows; the clinical value of multi-checkpoint and other combination strategies remains to be established.