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

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.