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  • Review Article
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Targeting phagocytosis checkpoints for cancer immunotherapy

Nature Reviews Cancer volume 26, pages 185–199 (2026)Cite this article

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Abstract

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.

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Fig. 1: Macrophage-mediated phagocytosis is a multistep process.
Fig. 2: Pro-phagocytic receptors facilitate engulfment of living cancer cells.
Fig. 3: Inhibitory phagocytic receptors prevent engulfment of living cancer cells.
Fig. 4: The anti-phagocytic SIRPα–CD47 interaction can be blocked using CD47 monoclonal antibodies or SIRPα monoclonal antibodies to promote tumour cell phagocytosis.

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Acknowledgements

Work in the laboratories of the authors has been supported by grants from the Canadian Institutes of Health Research (MT-14429, MOP-82906, FDN-143338, PJT-178314 and PJT-183593) and the Terry Fox Research Institute (1190-02) to A.V. and grants from the Science and Technology Development Fund (0090/2024/RIB2) and the University of Macau (SRG2024-00027-FHS and UMDF-TISF/2025/002/FHS) to Z.T.

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Authors and Affiliations

  1. Laboratory of Molecular Oncology, Institut de recherches cliniques de Montréal (IRCM), Montreal, Quebec, Canada

    André Veillette, Jiaxin Li, Cristian Camilo Galindo & Dominique Davidson

  2. Department of Medicine, McGill University, Montreal, Quebec, Canada

    André Veillette, Jiaxin Li & Cristian Camilo Galindo

  3. Department of Medicine, University of Montreal, Montreal, Quebec, Canada

    André Veillette

  4. Department of Biomedical Sciences, Faculty of Health Sciences, University of Macau, Macau SAR, China

    Zhenghai Tang

  5. MOE Frontiers Science Centre for Precision Oncology, Faculty of Health Sciences, University of Macau, Macau SAR, China

    Zhenghai Tang

  6. Cancer Centre, Faculty of Health Sciences, University of Macau, Macau SAR, China

    Zhenghai Tang

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  1. André Veillette
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Glossary

Agglutination

A reaction in which cells clump together, typically caused by the binding of a specific antibody.

Antibody-dependent cellular cytotoxicity

(ADCC). An immune mechanism wherein antibodies bind to their antigen (on an infected or cancerous cell), triggering activation of effector immune cells, such as natural killer (NK) cells and macrophages, to kill the target by releasing cytotoxic molecules.

Anti-inflammatory macrophages

A subtype of macrophage, also known as M2-like macrophage, that is induced by anti-inflammatory stimuli, such as IL-4 or IL-13, to promote tissue repair.

Apoptosis

A form of programmed cell death in which the cell actively participates, regulates and controls its death.

Basket trials

Clinical trials testing the effectiveness of a single drug on multiple types of cancer that share a common feature.

CD300 family

A group of immune cell surface receptors with inhibitory or activating functions that primarily recognize lipids as ligands.

Chimeric antigen receptor (CAR) T cells

A type of T cell collected from a patient, genetically modified to express a synthetic chimeric receptor that recognizes and destroys cancer cells.

C-type lectin receptor

A family of transmembrane proteins that act as pattern recognition receptors (PRRs) and mostly recognize carbohydrates as ligands.

ER stress

A cellular condition wherein the endoplasmic reticulum (ER) is overloaded with misfolded and unfolded proteins.

Homotypic receptor

Cell surface receptor that utilizes, as ligand, another molecule of the same receptor expressed on another cell or, sometimes, the same cell.

Immunogenic cell death

A type of cell death that triggers an immune response and leads to the release of damage-associated molecular patterns (DAMPs).

Immunoreceptor tyrosine-based activation motifs

(ITAMs). Conserved amino acid sequences found in the cytoplasmic domain of signalling chains and some cell surface receptors that consist of two YXXL/I repeats, in which Y is a tyrosine, x is any amino acid, L is a leucine and I is an isoleucine, separated by six to eight residues.

Immunoreceptor tyrosine-based inhibitory motifs

(ITIMs). Conserved amino acid sequences found in the cytoplasmic domain of many inhibitory cell surface receptors that consist of the sequence S/I/V/LXYXXI/V/, in which S is a serine, I is an isoleucine, V is a valine, L is a leucine, X is any amino acid, and Y is a tyrosine.

Immunoreceptor tyrosine-based switch motif

(ITSM). A conserved amino acid sequence found in the cytoplasmic domain of specific receptors of immune cells that consists of a tyrosine residue (Y) followed by two other amino acids (XX) and then a leucine or an isoleucine (L/I).

Lipid scrambling

A process carried out by lipid scramblases, which transport lipids across the membrane bilayer in both directions.

Macropinocytosis

A type of endocytosis characterized by the uptake of fluids and their dissolved substances in large vesicles named macropinosomes.

Myelodysplastic syndrome

(MDS). A group of disorders in which the production and maturation of blood cells are abnormal that often evolve into acute myelogenous leukaemia (AML).

P2Y2

A member of the family of G protein coupled receptors activated by its ligands ATP and UTP.

Pro-inflammatory macrophages

A subtype of macrophage, also known as M1-like macrophage, that is induced by inflammatory stimuli such as bacteria or virus components, some cytokines or tissue damage.

Pyroglutamation

An enzymatic reaction mediated by glutaminyl-peptide cyclotransferase-like protein (QPCTL), a Golgi-resident enzyme that catalyses the modification of amino-terminal glutamine and glutamic acid residues into amino-terminal pyroglutamate residues.

Sialic acid

A group of sugars with a backbone of nine carbons, localizing mainly at the end of sugar chains.

Signalling lymphocytic activation molecule family

A group of immune cell surface receptors including six canonical members (SLAM, Ly-9, 2B4, CD84, SLAMF6 and SLAMF7) and three non-canonical members (CD48, SLAMF8 and SLAMF9).

Small-molecule kinase inhibitors

Drugs that work by blocking the activity of kinases.

Stimulator of interferon genes (STING) pathway

A pathway of the innate immune system involved in the recognition of and response to foreign or self-derived DNA in the cytoplasm.

Transfusion compatibility testing

Routine test performed before administering blood or blood products that aims to detect the presence of antibodies in the recipient against blood components of the donor.

Trogocytosis

A cellular process wherein one cell physically extracts and ingests ‘bites’ of cellular material from another cell.

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Veillette, A., Li, J., Galindo, C.C. et al. Targeting phagocytosis checkpoints for cancer immunotherapy. Nat Rev Cancer 26, 185–199 (2026). https://doi.org/10.1038/s41568-025-00893-w

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