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The role of tumor-associated macrophages in tumor immune evasion

Huang, Ruizhe, Kang, Ting, Chen, Siyu·2024·Journal of Cancer Research and Clinical Oncology
DOI 10.1007/s00432-024-05777-4PMC PMC11076352
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Abstract

Background: Tumor growth is closely linked to the activities of various cells in the tumor microenvironment (TME), particularly immune cells. During tumor progression, circulating monocytes and macrophages are recruited, altering the TME and accelerating growth. These macrophages adjust their functions in response to signals from tumor and stromal cells. Tumor-associated macrophages (TAMs), similar to M2 macrophages, are key regulators in the TME. Methods: We review the origins, characteristics, and functions of TAMs within the TME. This analysis includes the mechanisms through which TAMs facilitate immune evasion and promote tumor metastasis. Additionally, we explore potential therapeutic strategies that target TAMs. Results: TAMs are instrumental in mediating tumor immune evasion and malignant behaviors. They release cytokines that inhibit effector immune cells and attract additional immunosuppressive cells to the TME. TAMs primarily target effector T cells, inducing exhaustion directly, influencing activity indirectly through cellular interactions, or suppressing through immune checkpoints. Additionally, TAMs are directly involved in tumor proliferation, angiogenesis, invasion, and metastasis. Summary: Developing innovative tumor-targeted therapies and immunotherapeutic strategies is currently a promising focus in oncology. Given the pivotal role of TAMs in immune evasion, several therapeutic approaches have been devised to target them. These include leveraging epigenetics, metabolic reprogramming, and cellular engineering to repolarize TAMs, inhibiting their recruitment and activity, and using TAMs as drug delivery vehicles. Although some of these strategies remain distant from clinical application, we believe that future therapies targeting TAMs will offer significant benefits to cancer patients.

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Fig. 1 TAMs are derived from monocytes in the bone marrow. Monocytes mature in the bone marrow and then migrate to the peripheral blood circulation. Recruited by CCL-2 chemokine signals, monocytes enter the TME and differentiate into macrophages under the influence of cytokines such as M-CSF and TGF-β. The macrophages then differentiate into two phenotypes, M1 and M2, stimulated by more cytokines in the TME, and ultimately exert specific effects on tumor cells and other immune cells within the TME. The image was created using https://www.biorender.com/
Fig. 1 TAMs are derived from monocytes in the bone marrow. Monocytes mature in the bone marrow and then migrate to the peripheral blood circulation. Recruited by CCL-2 chemokine signals, monocytes enter the TME and differentiate into macrophages under the influence of cytokines such as M-CSF and TGF-β. The macrophages then differentiate into two phenotypes, M1 and M2, stimulated by more cytokines in the TME, and ultimately exert specific effects on tumor cells and other immune cells within the TME. The image was created using https://www.biorender.com/CC BY · PubMed Central
Fig. 2 Four mechanisms of TAMs mediated tumor immune escape: a TAMs suppress anti-tumor immune cells and recruit immunosuppressive cells: Macrophages undergo polarization under the action of cytokines such as IL-10 and TGF-β, and modulate the function of Th1 cells, Tregs, and NK cells in the TME towards immunosuppression. TAMs can also recruit more immunosuppressive cells from the peripheral blood into the TME. b TAMs mediate cytotoxic T cell exhaustion: Tumor cells activate macrophages which are recognized by dendritic cells, and dendritic cells present tumor antigens to CTLs. TAMs can suppress the function of CTLs by expressing IFR8, ultimately leading to their exhaustion. c TAMs interact with MDSCs to induce immunosuppression: TAMs can mutually activate with MDSCs through IL-10 and activate Tergs cells. MDSCs suppress the function of T cells through various mechanisms, including the production of reactive oxygen species, reactive nitrogen species, and adenosine, ultimately leading to immunosuppression. d TAMs use immune checkpoints to reduce T cell function: Tumor cells and cancer stem cells activate TAMs through cytokine secretion, exosome production, and other pathways, and upregulate PD-L1 expression through signaling pathways such as NF-κB, TLR-7, and STAT3, ultimately preventing T cells from mounting an immune response against tumor cells. The image was created using https://www.biorender.com/
Fig. 2 Four mechanisms of TAMs mediated tumor immune escape: a TAMs suppress anti-tumor immune cells and recruit immunosuppressive cells: Macrophages undergo polarization under the action of cytokines such as IL-10 and TGF-β, and modulate the function of Th1 cells, Tregs, and NK cells in the TME towards immunosuppression. TAMs can also recruit more immunosuppressive cells from the peripheral blood into the TME. b TAMs mediate cytotoxic T cell exhaustion: Tumor cells activate macrophages which are recognized by dendritic cells, and dendritic cells present tumor antigens to CTLs. TAMs can suppress the function of CTLs by expressing IFR8, ultimately leading to their exhaustion. c TAMs interact with MDSCs to induce immunosuppression: TAMs can mutually activate with MDSCs through IL-10 and activate Tergs cells. MDSCs suppress the function of T cells through various mechanisms, including the production of reactive oxygen species, reactive nitrogen species, and adenosine, ultimately leading to immunosuppression. d TAMs use immune checkpoints to reduce T cell function: Tumor cells and cancer stem cells activate TAMs through cytokine secretion, exosome production, and other pathways, and upregulate PD-L1 expression through signaling pathways such as NF-κB, TLR-7, and STAT3, ultimately preventing T cells from mounting an immune response against tumor cells. The image was created using https://www.biorender.com/CC BY · PubMed Central

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Metadata

Authors
Huang, R., Kang, T., & Chen, S.
Venue
Journal of Cancer Research and Clinical Oncology
Publisher
Springer Science and Business Media LLC
Published
2024-05-07
Volume
150
Issue
5
ISSN
1432-1335
DOI
10.1007/s00432-024-05777-4
PMC
PMC11076352
Cited by
230
References
24
Language
en
Licence
Funders
National Natural Science Foundation of China (82074074, 82104447)

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