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  • Perspective
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A timeline of tumour-associated macrophage biology

Nature Reviews Cancer volume 23, pages 238–257 (2023)Cite this article

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Abstract

Tumour progression is modulated by the local microenvironment. This environment is populated by many immune cells, of which macrophages are among the most abundant. Clinical correlative data and a plethora of preclinical studies in mouse models of cancers have shown that tumour-associated macrophages (TAMs) play a cancer-promoting role. Within the primary tumour, TAMs promote tumour cell invasion and intravasation and tumour stem cell viability and induce angiogenesis. At the metastatic site, metastasis-associated macrophages promote extravasation, tumour cell survival and persistent growth, as well as maintain tumour cell dormancy in some contexts. In both the primary and metastatic sites, TAMs are suppressive to the activities of cytotoxic T and natural killer cells that have the potential to eradicate tumours. Such activities suggest that TAMs will be a major target for therapeutic intervention. In this Perspective article, we chronologically explore the evolution of our understanding of TAM biology put into the context of major enabling advances in macrophage biology.

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Fig. 1: A timeline of macrophage-related research that has paved the way for understanding the tumour microenvironment.
Fig. 2: Discoveries relating to tumour-associated macrophage and metastasis-associated macrophage pro-tumoural functions in breast cancer.
Fig. 3: Cellular interactions of tumour-associated macrophages in the tumour microenvironment.
Fig. 4: Tumour-associated macrophage targeting drugs entering the clinic.

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Acknowledgements

The authors thank The Wellcome Trust 101067/Z/13/Z (J.W.P.), MRC Centre grant MR/N022556/1 (J.W.P.) and CRUK programme grant C17950/A26783 (J.W.P.). The authors also thank C. Ries for her valuable insights on TAM targeting strategies.

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  1. Macomics Ltd, Edinburgh, UK

    Luca Cassetta

  2. MRC-Centre for Reproductive Health, Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, UK

    Jeffrey W. Pollard

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The authors contributed equally to all aspects of the article.

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Correspondence to Jeffrey W. Pollard.

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J.W.P. is a cofounder and shareholder in and on the board of Macomics, an immuno-oncology company. L.C. is a founder, shareholder and is VP Immunology for Macomics.

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Glossary

Adaptive immune responses

The immune response mediated by recognition of non-self by lymphocytes, leading to an antigen-specific immune response and the generation of memory cells that fight against future infections.

CD40

(Cluster of differentiation 40). This member of the tumour necrosis factor receptor family is a costimulatory protein found on antigen-presenting cells and is required for their activation.

Chemokines

Small chemotactic signalling proteins secreted by cells to induce migration of stromal and cancerous cells to facilitate homeostasis and tissue repair.

Complement activation

A part of the immune system that enhances (complements) the ability of antibodies and phagocytic cells to clear microorganisms and damaged cells from an organism, promote inflammation and attack the cell membrane of the pathogen.

Dendritic cells

Phagocytic mononuclear cells with finger-like projections that are specialized in migration and antigen presentation.

Humoral immunity

Adaptive immunity that is mediated by B cell-derived antibodies and macromolecules, including complement proteins, and certain antimicrobial peptides, located in extracellular fluids.

Innate immune system

The first response of the body to foreign substrates; it is not antigen recognition-driven, requires sensing of pattern molecules (either damage-associated or pathogen-associated) and can modulate the cells of the second immunity strategy (adaptive immunity).

Lymphoreticular infiltration

The presence of bone marrow progenitors, blood monocytes, tissue macrophages, lymphocytes, plasma cells, polymorphonuclear leukocytes and mast cells in the tumour.

M1 macrophages

Generally referred to as ‘activated’ macrophages, M1 are responsive to interferon-γ and lipopolysaccharide, and often considered antitumoural.

M2 macrophages

Generally known as ‘alternatively activated’ macrophages, M2 responds to IL-4 and IL-10 and typically regarded as pro-tumoural.

Monocytes

Bone marrow-derived progenitors of macrophages and a subset of dendritic cells, found in the circulation, and classified by their differentiation (classical, intermediate and non-classical).

Mononuclear phagocytes

(MNPs). Phagocytic cells belonging to the immune system and derived from the bone marrow, mostly monocytes and macrophages.

Mouse mammary tumour virus-polyoma middle tumour-antigen

(MMTV-PyMT). Mouse model of mammary cancer caused by expression of the PyMT oncoprotein in a mammary epithelial-restricted fashion; this model is autochthonous, progressive and metastatic.

Myeloid

Bone-marrow-derived cells from myeloblasts include basophils, eosinophils, neutrophils and macrophages.

Tenosynovial giant cell tumour

Non-malignant tumours in humans that often develop in the synovium caused by an activating gene translocation in the colony-stimulating factor 1 gene (CSF1) that results in excessive CSF1 production and thus infiltration of macrophages.

TH1

On the basis of extremes of immune responses, TH1 response is characterized by the production of interferon-γ, IL-2 and IL-12 and the ability to respond to bacterial and viral pathogens. TH1 responses generally confer cancer resistance.

TH2

TH2 responses characterized by production of IL-4, IL-5 and IL-10, and their role in tissue repair. TH2 responses generally confer cancer susceptibility.

Tumour microenvironment

(TME). The non-cancerous portion surrounding the tumour consisting of fibroblast, endothelial and immune cells as well as extracellular matrix and blood vessels (also referred to as ‘stroma’).

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Cassetta, L., Pollard, J.W. A timeline of tumour-associated macrophage biology. Nat Rev Cancer 23, 238–257 (2023). https://doi.org/10.1038/s41568-022-00547-1

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