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Peer-reviewedCC BY 4.0Frontiers in Immunology

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

  • Jie Li1,2
  • Mei Ding1,2
  • Jian Sun1,2
  • Lu Gao1,2
  • Zhencang Zhou1,2
  • Qian Zeng1,2
  • Fang Xu1,2
  • Siming Li1,2
  • Zuochen Du1,2
  • Pei Huang1,2,3
  • Yan Chen1,2,3
  1. 1Department of Pediatrics, Affiliated Hospital of Zunyi Medical University
  2. 2Guizhou Children’s Hospital
  3. 3Guizhou Biomanufacturing Laboratory, Affiliated Hospital of Zunyi Medical University
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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.

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Cite

BibTeXRIS
BibTeX
@article{li2026targeting,
  title = {{Targeting inhibitory phagocytosis checkpoints in cancer immunotherapy: mechanisms, therapeutic strategies, and translational challenges}},
  author = {Jie Li and Mei Ding and Jian Sun and Lu Gao and Zhencang Zhou and Qian Zeng and Fang Xu and Siming Li and Zuochen Du and Pei Huang and Yan Chen},
  journal = {Frontiers in Immunology},
  year = {2026},
  month = oct,
  doi = {10.3389/fimmu.2026.1924227},
  url = {https://www.frontiersin.org/articles/10.3389/fimmu.2026.1924227/full},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Targeting inhibitory phagocytosis checkpoints in cancer immunotherapy: mechanisms, therapeutic strategies, and translational challenges
AU  - Jie Li
AU  - Mei Ding
AU  - Jian Sun
AU  - Lu Gao
AU  - Zhencang Zhou
AU  - Qian Zeng
AU  - Fang Xu
AU  - Siming Li
AU  - Zuochen Du
AU  - Pei Huang
AU  - Yan Chen
PY  - 2026
DA  - 2026/10/13
JO  - Frontiers in Immunology
DO  - 10.3389/fimmu.2026.1924227
UR  - https://www.frontiersin.org/articles/10.3389/fimmu.2026.1924227/full
AB  - 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.
SN  - 1664-3224
ER  -