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Review
. 2023 Dec 29;16(1):61.
doi: 10.3390/pharmaceutics16010061.

Tumor-Associated Macrophage Targeting of Nanomedicines in Cancer Therapy

Xuejia Kang  1   2 , Yongzhuo Huang  3   4 , Huiyuan Wang  4 , Sanika Jadhav  5 , Zongliang Yue  6 , Amit K Tiwari  7 , R Jayachandra Babu  1
Affiliations
Review

Tumor-Associated Macrophage Targeting of Nanomedicines in Cancer Therapy

Xuejia Kang et al. Pharmaceutics. .

Abstract

The tumor microenvironment (TME) is pivotal in tumor growth and metastasis, aligning with the "Seed and Soil" theory. Within the TME, tumor-associated macrophages (TAMs) play a central role, profoundly influencing tumor progression. Strategies targeting TAMs have surfaced as potential therapeutic avenues, encompassing interventions to block TAM recruitment, eliminate TAMs, reprogram M2 TAMs, or bolster their phagocytic capabilities via specific pathways. Nanomaterials including inorganic materials, organic materials for small molecules and large molecules stand at the forefront, presenting significant opportunities for precise targeting and modulation of TAMs to enhance therapeutic efficacy in cancer treatment. This review provides an overview of the progress in designing nanoparticles for interacting with and influencing the TAMs as a significant strategy in cancer therapy. This comprehensive review presents the role of TAMs in the TME and various targeting strategies as a promising frontier in the ever-evolving field of cancer therapy. The current trends and challenges associated with TAM-based therapy in cancer are presented.

Keywords: nanomedicine; suppressive immune environment; targeted delivery systems; tumor proliferation and metastasis; tumor-associated macrophage.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 7
Figure 7
Nanotechnology-based strategies for reprogramming tumor microenvironment. (A) Remodeling tumor-associated macrophages and neovascularization overcomes EGFRT790M-associated drug resistance by PD-L1 nanobody-mediated codelivery of Gefitinib and Simvastatin [224]. Copyright © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim, Germany. (B) Reprogramming tumor-associated macrophages to reverse EGFRT790M resistance by dual-targeting codelivery of gefitinib/vorinostat [239]. Copyright © 2017 American Chemical Society (↑ suggesting the increase, ↓ suggest the decrease). (C) Targeting lipid metabolism to overcome EMT-associated drug resistance via integrin β3/FAK pathway and tumor-associated macrophage repolarization using legumain-activatable delivery [249]. This is an open-access article distributed under the terms of the Creative Commons Attribution License.
Figure 1
Figure 1
In the tumor niche, tumor cells release MCSF, IL4, and IL10, etc., to attract macrophage; then, tumor-associated macrophages engage in intricate interactions with cancer-associated fibroblasts (CAFs), T regulatory cells, natural killer cells to form an immunosuppressive tumor microenvironment (TME). Understanding these interactions is crucial for developing targeted therapies to overcome immunosuppression in the TME. (Images created with biorender.com, accessed on 17 July 2023).
Figure 2
Figure 2
The role of macrophages in TME: In the context of tumor progression, neoplastic cells and stromal cells release specific molecules that act as chemoattractants, such as CCL2 and MCSF-1, to recruit circulating monocytes to the tumor site. Once recruited, monocytes significantly differentiate into M2 TAMs. The predominant M2 TAMs promote the downregulation of tumor immunity, angiogenesis, as well as therapeutic resistance (↓ suggesting decrease) (created with biorender.com, accessed on 17 July 2023).
Figure 3
Figure 3
Schematic representation of a variety of therapeutic approaches targeting TAM. Targeting TAMs therapeutic strategies involve inhibiting TAM recruitment and differentiation, depleting or impairing their function, reprogramming M2 TAMs, and promoting their phagocytic activity. Inhibiting TAM recruitment entails blocking chemokine and growth factor signaling while inhibiting TAM differentiation involves targeting factors like IL-4 and IL-13. Depleting TAMs can be achieved through selective elimination using specific markers or immunotherapies. Impairing TAM function targets signaling pathways involved in immunosuppression and angiogenesis. Reprogramming M2 TAMs toward an anti-tumoral M1-like phenotype enhances their anti-tumor activity. Promoting TAM phagocytosis enhances their ability to eliminate tumor cells. Combination therapies, integrating TAM-targeting approaches with other modalities, hold promise for synergistic effects (Created with biorender.com, accessed on 17 July 2023).
Figure 4
Figure 4
Represenative of therapeutic modality for metabolism in TAM. (A) Schematic illustration of biomimetic targeting codelivery of Shikonin/JQ1 for reprogramming TME via regulation of metabolism (↑ suggesting increase, ↓ suggesting decrease) [180]. Copyright © 2019 American Chemical Society. (B) Schematic illustration of anti-alcoholism drug disulfiram for targeting glioma energy metabolism [178]. Copyright © 2022 Published by Elsevier Ltd. (C) Schematic illustration of using a PD-L1-targeting system loaded with rapamycin and regorafenib for metabolic modulation in TME [182]. Copyright © 2020 Elsevier Ltd.
Figure 5
Figure 5
Representative work of inorganic nanomaterials for TAM modality. (A) Schematic illustration of AuNC-based in situ vaccination: the photothermal tumor ablation of AuNC cut the source of TAM differentiation; the combination of AuNCs with the JQ1 (PD-L1 suppressor) dramatically inhibit the function of M2 TAM that overexpress PD-L1 [197]. Copyright © 2022 American Chemical Society. (B) Graphdiyne oxide nanosheets reprogram immunosuppressive macrophages for cancer immunotherapy (↑ suggesting the increase, ↓ suggesting the decrease) [204]. Copyright © 2022 Elsevier Ltd.
Figure 6
Figure 6
Representative work of inorganic nanomaterials for TAM modality. (A) Schematic representation of recombinant cell-penetrating trichosanthin synergizes anti-PD-1 therapy in colorectal tumor [208]. This is an open-access article distributed under the terms of the Creative Commons Attribution License. (B) Schematic representation of using mannose-modified system for mRNA delivery. Reproduced from reference [210]. Open-access article distributed under the terms of the Creative Commons CC BY license. (C) Schematic representation of using erythrocyte membrane-coated virus-mimicking nanogel for miRNA delivery [210]. Copyright © 2021 John Wiley and Sons.
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References

    1. Fidler I.J., Poste G. The “seed and soil” hypothesis revisited. Lancet Oncol. 2008;9:808. doi: 10.1016/S1470-2045(08)70201-8. - DOI - PubMed
    1. Nielsen S.R., Schmid M.C. Macrophages as Key Drivers of Cancer Progression and Metastasis. Mediat. Inflamm. 2017;2017:9624760. doi: 10.1155/2017/9624760. - DOI - PMC - PubMed
    1. Gutmann D.H., Kettenmann H. Microglia/Brain Macrophages as Central Drivers of Brain Tumor Pathobiology. Neuron. 2019;104:442–449. doi: 10.1016/j.neuron.2019.08.028. - DOI - PMC - PubMed
    1. Liu X., Liu Y., Qi Y., Huang Y., Hu F., Dong F., Shu K., Lei T. Signal Pathways Involved in the Interaction between Tumor-Associated Macrophages/TAMs and Glioblastoma Cells. Front. Oncol. 2022;12:822085. doi: 10.3389/fonc.2022.822085. - DOI - PMC - PubMed
    1. Amer H.T., Stein U., El Tayebi H.M. The monocyte, a maestro in the tumor microenvironment (TME) of breast cancer. Cancers. 2022;14:5460. doi: 10.3390/cancers14215460. - DOI - PMC - PubMed

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