Targeting RARγ Decreases Immunosuppressive Macrophage Polarization and Reduces Tumor Growth
Tumor-associated macrophages (TAMs) play a critical role in the tumor microenvironment (TME), interacting with cancer cells and other components to promote tumor growth. Given the influence of TAMs on tumor progression and resistance to therapy, regulating the activity of these macrophages is crucia...
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| Format: | Article |
| Language: | English |
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MDPI AG
2025-07-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/30/15/3099 |
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| author | Jihyeon Park Jisun Oh Sang-Hyun Min Ji Hoon Yu Jong-Sup Bae Hui-Jeon Jeon |
| author_facet | Jihyeon Park Jisun Oh Sang-Hyun Min Ji Hoon Yu Jong-Sup Bae Hui-Jeon Jeon |
| author_sort | Jihyeon Park |
| collection | DOAJ |
| description | Tumor-associated macrophages (TAMs) play a critical role in the tumor microenvironment (TME), interacting with cancer cells and other components to promote tumor growth. Given the influence of TAMs on tumor progression and resistance to therapy, regulating the activity of these macrophages is crucial for improving cancer treatment outcomes. TAMs often exhibit immunosuppressive phenotypes (commonly referred to as M2-like macrophages), which suppress immune responses and contribute to drug resistance. Therefore, inhibiting immunosuppressive polarization offers a promising strategy to impede tumor growth. This study revealed retinoic acid receptor gamma (RARγ), a nuclear receptor, as a key regulator of immunosuppressive polarization in THP-1 macrophages. Indeed, the inhibition of RARγ, either by a small molecule or gene silencing, significantly reduced the expression of immunosuppressive macrophage markers. In a three-dimensional tumor spheroid model, immunosuppressive macrophages enhanced the proliferation of HCT116 colorectal cancer cells, which was significantly hindered by RARγ inhibition. These findings suggest that targeting RARγ reprograms immunosuppressive macrophages and mitigates the tumor-promoting effects of TAMs, highlighting RARγ as a promising therapeutic target for developing novel anti-cancer strategies. |
| format | Article |
| id | doaj-art-5b95147fa4b8498189e3d3f5b48e2ea9 |
| institution | DOAJ |
| issn | 1420-3049 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj-art-5b95147fa4b8498189e3d3f5b48e2ea92025-08-20T03:02:55ZengMDPI AGMolecules1420-30492025-07-013015309910.3390/molecules30153099Targeting RARγ Decreases Immunosuppressive Macrophage Polarization and Reduces Tumor GrowthJihyeon Park0Jisun Oh1Sang-Hyun Min2Ji Hoon Yu3Jong-Sup Bae4Hui-Jeon Jeon5College of Pharmacy, Kyungpook National University, Daegu 41566, Republic of KoreaNew Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation (K-MEDI hub), Daegu 41061, Republic of KoreaDepartment of Innovative Pharmaceutical Sciences, Kyungpook National University, Daegu 41566, Republic of KoreaNew Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation (K-MEDI hub), Daegu 41061, Republic of KoreaCollege of Pharmacy, Kyungpook National University, Daegu 41566, Republic of KoreaNew Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation (K-MEDI hub), Daegu 41061, Republic of KoreaTumor-associated macrophages (TAMs) play a critical role in the tumor microenvironment (TME), interacting with cancer cells and other components to promote tumor growth. Given the influence of TAMs on tumor progression and resistance to therapy, regulating the activity of these macrophages is crucial for improving cancer treatment outcomes. TAMs often exhibit immunosuppressive phenotypes (commonly referred to as M2-like macrophages), which suppress immune responses and contribute to drug resistance. Therefore, inhibiting immunosuppressive polarization offers a promising strategy to impede tumor growth. This study revealed retinoic acid receptor gamma (RARγ), a nuclear receptor, as a key regulator of immunosuppressive polarization in THP-1 macrophages. Indeed, the inhibition of RARγ, either by a small molecule or gene silencing, significantly reduced the expression of immunosuppressive macrophage markers. In a three-dimensional tumor spheroid model, immunosuppressive macrophages enhanced the proliferation of HCT116 colorectal cancer cells, which was significantly hindered by RARγ inhibition. These findings suggest that targeting RARγ reprograms immunosuppressive macrophages and mitigates the tumor-promoting effects of TAMs, highlighting RARγ as a promising therapeutic target for developing novel anti-cancer strategies.https://www.mdpi.com/1420-3049/30/15/3099tumor microenvironmenttumor-associated macrophagesM2 polarizationretinoic acid receptor gammatherapeutic target |
| spellingShingle | Jihyeon Park Jisun Oh Sang-Hyun Min Ji Hoon Yu Jong-Sup Bae Hui-Jeon Jeon Targeting RARγ Decreases Immunosuppressive Macrophage Polarization and Reduces Tumor Growth Molecules tumor microenvironment tumor-associated macrophages M2 polarization retinoic acid receptor gamma therapeutic target |
| title | Targeting RARγ Decreases Immunosuppressive Macrophage Polarization and Reduces Tumor Growth |
| title_full | Targeting RARγ Decreases Immunosuppressive Macrophage Polarization and Reduces Tumor Growth |
| title_fullStr | Targeting RARγ Decreases Immunosuppressive Macrophage Polarization and Reduces Tumor Growth |
| title_full_unstemmed | Targeting RARγ Decreases Immunosuppressive Macrophage Polarization and Reduces Tumor Growth |
| title_short | Targeting RARγ Decreases Immunosuppressive Macrophage Polarization and Reduces Tumor Growth |
| title_sort | targeting rarγ decreases immunosuppressive macrophage polarization and reduces tumor growth |
| topic | tumor microenvironment tumor-associated macrophages M2 polarization retinoic acid receptor gamma therapeutic target |
| url | https://www.mdpi.com/1420-3049/30/15/3099 |
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