Dual targeting of tumoral cells and immune microenvironment by blocking the IL-33/IL1RL1 pathway
Abstract Leukemia stem cells (LSCs) are a small yet powerful subset of leukemic cells that possess the ability to self-renew and have a long-term tumorigenic capacity, playing a crucial role in both leukemia development and therapy resistance. These LSCs are influenced by external and internal facto...
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| Format: | Article |
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Nature Portfolio
2025-07-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-61567-7 |
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| author | Denggang Fu Hua Jiang Alan Long Ella Harris Hongfen Guo Maegan L. Capitano John Wrangle Joshua R. Faust Anilkumar Gopalakrishnapillai Santhosh Kumar Pasupuleti Baskar Ramdas Reuben Kapur Sonali P. Barwe Nai-Kong V. Cheung Sophie Paczesny |
| author_facet | Denggang Fu Hua Jiang Alan Long Ella Harris Hongfen Guo Maegan L. Capitano John Wrangle Joshua R. Faust Anilkumar Gopalakrishnapillai Santhosh Kumar Pasupuleti Baskar Ramdas Reuben Kapur Sonali P. Barwe Nai-Kong V. Cheung Sophie Paczesny |
| author_sort | Denggang Fu |
| collection | DOAJ |
| description | Abstract Leukemia stem cells (LSCs) are a small yet powerful subset of leukemic cells that possess the ability to self-renew and have a long-term tumorigenic capacity, playing a crucial role in both leukemia development and therapy resistance. These LSCs are influenced by external and internal factors within the bone marrow niche. By delving into the intricate interplay between LSCs and their immune environment, we can pave the way for innovative immunotherapies that target both the malignant stem cells and the suppressive immune microenvironment, addressing both the “seed” and the “soil” simultaneously. Through the analysis of public datasets and patient samples, we show that elevated IL1RL1 expression correlates with poor prognosis and therapy resistance in acute myeloid leukemia (AML). At the core of this process, stem cell leukemogenesis initiation and maintenance signals are driven by a stress-induced IL-33/IL1RL1 autocrine loop. This LSC-induced IL-33/IL1RL1 signaling fosters an immune regulatory microenvironment. Therefore, IL1RL1 emerges as a promising therapeutic target, with IL1RL1-specific T cell-engaging bispecific antibodies holding great potential as cutting-edge immunotherapeutics for AML. |
| format | Article |
| id | doaj-art-6687d4cd6f9b429e9f411746c11278fc |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-6687d4cd6f9b429e9f411746c11278fc2025-08-20T03:46:11ZengNature PortfolioNature Communications2041-17232025-07-0116112110.1038/s41467-025-61567-7Dual targeting of tumoral cells and immune microenvironment by blocking the IL-33/IL1RL1 pathwayDenggang Fu0Hua Jiang1Alan Long2Ella Harris3Hongfen Guo4Maegan L. Capitano5John Wrangle6Joshua R. Faust7Anilkumar Gopalakrishnapillai8Santhosh Kumar Pasupuleti9Baskar Ramdas10Reuben Kapur11Sonali P. Barwe12Nai-Kong V. Cheung13Sophie Paczesny14Department of Microbiology and Immunology and Pediatrics, Medical University of South CarolinaDepartment of Microbiology and Immunology and Pediatrics, Medical University of South CarolinaDepartment of Pediatrics, Memorial Sloan Kettering Cancer CenterDepartment of Microbiology and Immunology and Pediatrics, Medical University of South CarolinaDepartment of Pediatrics, Memorial Sloan Kettering Cancer CenterDepartment of Pediatrics, Indiana University School of MedicineDepartment of Microbiology and Immunology and Medicine, Medical University of South CarolinaNemours Children’s Hospital, Lisa Dean Moseley Foundation Institute of Cancer and Blood DisordersNemours Children’s Hospital, Lisa Dean Moseley Foundation Institute of Cancer and Blood DisordersDepartment of Pediatrics, Indiana University School of MedicineDepartment of Pediatrics, Indiana University School of MedicineDepartment of Pediatrics, Indiana University School of MedicineNemours Children’s Hospital, Lisa Dean Moseley Foundation Institute of Cancer and Blood DisordersDepartment of Pediatrics, Memorial Sloan Kettering Cancer CenterDepartment of Microbiology and Immunology and Pediatrics, Medical University of South CarolinaAbstract Leukemia stem cells (LSCs) are a small yet powerful subset of leukemic cells that possess the ability to self-renew and have a long-term tumorigenic capacity, playing a crucial role in both leukemia development and therapy resistance. These LSCs are influenced by external and internal factors within the bone marrow niche. By delving into the intricate interplay between LSCs and their immune environment, we can pave the way for innovative immunotherapies that target both the malignant stem cells and the suppressive immune microenvironment, addressing both the “seed” and the “soil” simultaneously. Through the analysis of public datasets and patient samples, we show that elevated IL1RL1 expression correlates with poor prognosis and therapy resistance in acute myeloid leukemia (AML). At the core of this process, stem cell leukemogenesis initiation and maintenance signals are driven by a stress-induced IL-33/IL1RL1 autocrine loop. This LSC-induced IL-33/IL1RL1 signaling fosters an immune regulatory microenvironment. Therefore, IL1RL1 emerges as a promising therapeutic target, with IL1RL1-specific T cell-engaging bispecific antibodies holding great potential as cutting-edge immunotherapeutics for AML.https://doi.org/10.1038/s41467-025-61567-7 |
| spellingShingle | Denggang Fu Hua Jiang Alan Long Ella Harris Hongfen Guo Maegan L. Capitano John Wrangle Joshua R. Faust Anilkumar Gopalakrishnapillai Santhosh Kumar Pasupuleti Baskar Ramdas Reuben Kapur Sonali P. Barwe Nai-Kong V. Cheung Sophie Paczesny Dual targeting of tumoral cells and immune microenvironment by blocking the IL-33/IL1RL1 pathway Nature Communications |
| title | Dual targeting of tumoral cells and immune microenvironment by blocking the IL-33/IL1RL1 pathway |
| title_full | Dual targeting of tumoral cells and immune microenvironment by blocking the IL-33/IL1RL1 pathway |
| title_fullStr | Dual targeting of tumoral cells and immune microenvironment by blocking the IL-33/IL1RL1 pathway |
| title_full_unstemmed | Dual targeting of tumoral cells and immune microenvironment by blocking the IL-33/IL1RL1 pathway |
| title_short | Dual targeting of tumoral cells and immune microenvironment by blocking the IL-33/IL1RL1 pathway |
| title_sort | dual targeting of tumoral cells and immune microenvironment by blocking the il 33 il1rl1 pathway |
| url | https://doi.org/10.1038/s41467-025-61567-7 |
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