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Modulating tumor-associated macrophages to enhance the efficacy of immune checkpoint inhibitors: A TAM-pting approach

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PHARMACOLOGY & THERAPEUTICS
卷 231, 期 -, 页码 -

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PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.pharmthera.2021.107986

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ICI (immune checkpoint inhibitors); Macrophage; M1; M2; TAM (tumor-associated macrophages); TME (tumor microenvironment)

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The plasticity and diversity of tumor-associated macrophages (TAM) play essential roles in cancer progression. TAM can shift their polarization in response to tumor microenvironment cues, promoting or halting cancer development. However, TAM's immunosuppressive functions contribute to resistance to immune checkpoint inhibitors (ICI). Targeting TAM modulation in combination with ICI shows potential for optimizing ICI efficacy.
Tumor-associated macrophages (TAM) plasticity and diversity are both essential hallmarks of the monocyte-macrophage lineage and the tumor-derived inflammation. TAM exemplify the perfect adaptable cell with dynamic phenotypic modifications that reflect changes in their functional polarization status. Under several tumor microenvironment (TME)-related cues, TAM shift their polarization, hence promoting or halting cancer progression. Immune checkpoint inhibitors (ICI) displayed unprecedented clinical responses in various refrac-tory cancers; but only approximately a third of patients experienced durable responses. It is, therefore, crucial to enhance the response rate of immunotherapy. Several mechanisms of resistance to ICI have been elucidated including TAM role with its essential immunosuppressive functions that reduce both anti-tumor immunity and the subsequent ICI efficacy. In the past few years, thorough research has led to a better understanding of TAM bi-ology and innovative approaches can now be adapted through targeting macrophages' recruitment axis as well as TAM activation and polarization status within the TME. Some of these therapeutic strategies are currently being evaluated in several clinical trials in association with ICI agents. This combination between TAM modulation and ICI allows targeting TAM intrinsic immunosuppressive functions and tumor-promoting factors as well as over-coming ICI resistance. Hence, such strategies, with a better understanding of the mechanisms driving TAM modulation, may have the potential to optimize ICI efficacy. (c) 2021 Published by Elsevier Inc.

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