Novel Arf1 Inhibitors Drive Cancer Stem Cell Aging and Potentiate Anti‐Tumor Immunity
Abstract The small G protein Arf1 has been identified as playing a selective role in supporting cancer stem cells (CSCs), making it an attractive target for cancer therapy. However, the current Arf1 inhibitors have limited translational potential due to their high toxicity and low specificity. In th...
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Wiley
2024-10-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202404442 |
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| author | Yuetong Wang Qiaoming Li Yahui Ding Chenfei Luo Jun Yang Na Wang Ning Jiang Tiange Yao Guohao Wang Guoming Shi Steven X. Hou |
| author_facet | Yuetong Wang Qiaoming Li Yahui Ding Chenfei Luo Jun Yang Na Wang Ning Jiang Tiange Yao Guohao Wang Guoming Shi Steven X. Hou |
| author_sort | Yuetong Wang |
| collection | DOAJ |
| description | Abstract The small G protein Arf1 has been identified as playing a selective role in supporting cancer stem cells (CSCs), making it an attractive target for cancer therapy. However, the current Arf1 inhibitors have limited translational potential due to their high toxicity and low specificity. In this study, two new potent small‐molecule inhibitors of Arf1, identified as DU101 and DU102, for cancer therapy are introduced. Preclinical tumor models demonstrate that these inhibitors triggered a cascade of aging in CSCs and enhance anti‐tumor immunity in mouse cancer and PDX models. Through single‐cell sequencing, the remodeling of the tumor immune microenvironment induced by these new Arf1 inhibitors is analyzed and an increase in tumor‐associated CD8+ CD4+ double‐positive T (DPT) cells is identified. These DPT cells exhibit superior features of active CD8 single‐positive T cells and a higher percentage of TCF1+PD‐1+, characteristic of stem‐like T cells. The frequency of tumor‐infiltrating stem‐like DPT cells correlates with better disease‐free survival (DFS) in cancer patients, indicating that these inhibitors may offer a novel cancer immunotherapy strategy by converting the cold tumor immune microenvironment into a hot one, thus expanding the potential for immunotherapy in cancer patients. |
| format | Article |
| id | doaj-art-3123fbd059c74f3b8874b217b59b7168 |
| institution | OA Journals |
| issn | 2198-3844 |
| language | English |
| publishDate | 2024-10-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj-art-3123fbd059c74f3b8874b217b59b71682025-08-20T02:10:42ZengWileyAdvanced Science2198-38442024-10-011139n/an/a10.1002/advs.202404442Novel Arf1 Inhibitors Drive Cancer Stem Cell Aging and Potentiate Anti‐Tumor ImmunityYuetong Wang0Qiaoming Li1Yahui Ding2Chenfei Luo3Jun Yang4Na Wang5Ning Jiang6Tiange Yao7Guohao Wang8Guoming Shi9Steven X. Hou10Department of Cell and Developmental Biology at School of Life Sciences State Key Laboratory of Genetic Engineering Institute of Metabolism and Integrative Biology Human Phenome Institute Department of Liver Surgery and Transplantation of Liver Cancer Institute at Zhongshan Hospital Fudan University Shanghai 200438 ChinaDepartment of Cell and Developmental Biology at School of Life Sciences State Key Laboratory of Genetic Engineering Institute of Metabolism and Integrative Biology Human Phenome Institute Department of Liver Surgery and Transplantation of Liver Cancer Institute at Zhongshan Hospital Fudan University Shanghai 200438 ChinaDepartment of Cell and Developmental Biology at School of Life Sciences State Key Laboratory of Genetic Engineering Institute of Metabolism and Integrative Biology Human Phenome Institute Department of Liver Surgery and Transplantation of Liver Cancer Institute at Zhongshan Hospital Fudan University Shanghai 200438 ChinaDepartment of Cell and Developmental Biology at School of Life Sciences State Key Laboratory of Genetic Engineering Institute of Metabolism and Integrative Biology Human Phenome Institute Department of Liver Surgery and Transplantation of Liver Cancer Institute at Zhongshan Hospital Fudan University Shanghai 200438 ChinaDepartment of Cell and Developmental Biology at School of Life Sciences State Key Laboratory of Genetic Engineering Institute of Metabolism and Integrative Biology Human Phenome Institute Department of Liver Surgery and Transplantation of Liver Cancer Institute at Zhongshan Hospital Fudan University Shanghai 200438 ChinaDepartment of Cell and Developmental Biology at School of Life Sciences State Key Laboratory of Genetic Engineering Institute of Metabolism and Integrative Biology Human Phenome Institute Department of Liver Surgery and Transplantation of Liver Cancer Institute at Zhongshan Hospital Fudan University Shanghai 200438 ChinaDepartment of Cell and Developmental Biology at School of Life Sciences State Key Laboratory of Genetic Engineering Institute of Metabolism and Integrative Biology Human Phenome Institute Department of Liver Surgery and Transplantation of Liver Cancer Institute at Zhongshan Hospital Fudan University Shanghai 200438 ChinaDepartment of Cell and Developmental Biology at School of Life Sciences State Key Laboratory of Genetic Engineering Institute of Metabolism and Integrative Biology Human Phenome Institute Department of Liver Surgery and Transplantation of Liver Cancer Institute at Zhongshan Hospital Fudan University Shanghai 200438 ChinaThe Basic Research Laboratory Center for Cancer Research National Cancer Institute at Frederick National Institutes of Health Frederick MD 21702 USADepartment of Cell and Developmental Biology at School of Life Sciences State Key Laboratory of Genetic Engineering Institute of Metabolism and Integrative Biology Human Phenome Institute Department of Liver Surgery and Transplantation of Liver Cancer Institute at Zhongshan Hospital Fudan University Shanghai 200438 ChinaDepartment of Cell and Developmental Biology at School of Life Sciences State Key Laboratory of Genetic Engineering Institute of Metabolism and Integrative Biology Human Phenome Institute Department of Liver Surgery and Transplantation of Liver Cancer Institute at Zhongshan Hospital Fudan University Shanghai 200438 ChinaAbstract The small G protein Arf1 has been identified as playing a selective role in supporting cancer stem cells (CSCs), making it an attractive target for cancer therapy. However, the current Arf1 inhibitors have limited translational potential due to their high toxicity and low specificity. In this study, two new potent small‐molecule inhibitors of Arf1, identified as DU101 and DU102, for cancer therapy are introduced. Preclinical tumor models demonstrate that these inhibitors triggered a cascade of aging in CSCs and enhance anti‐tumor immunity in mouse cancer and PDX models. Through single‐cell sequencing, the remodeling of the tumor immune microenvironment induced by these new Arf1 inhibitors is analyzed and an increase in tumor‐associated CD8+ CD4+ double‐positive T (DPT) cells is identified. These DPT cells exhibit superior features of active CD8 single‐positive T cells and a higher percentage of TCF1+PD‐1+, characteristic of stem‐like T cells. The frequency of tumor‐infiltrating stem‐like DPT cells correlates with better disease‐free survival (DFS) in cancer patients, indicating that these inhibitors may offer a novel cancer immunotherapy strategy by converting the cold tumor immune microenvironment into a hot one, thus expanding the potential for immunotherapy in cancer patients.https://doi.org/10.1002/advs.202404442anti‐tumor immunityArf1 inhibitorcancer stem cellsuperior T cellstrans‐cellular signaling |
| spellingShingle | Yuetong Wang Qiaoming Li Yahui Ding Chenfei Luo Jun Yang Na Wang Ning Jiang Tiange Yao Guohao Wang Guoming Shi Steven X. Hou Novel Arf1 Inhibitors Drive Cancer Stem Cell Aging and Potentiate Anti‐Tumor Immunity Advanced Science anti‐tumor immunity Arf1 inhibitor cancer stem cell superior T cells trans‐cellular signaling |
| title | Novel Arf1 Inhibitors Drive Cancer Stem Cell Aging and Potentiate Anti‐Tumor Immunity |
| title_full | Novel Arf1 Inhibitors Drive Cancer Stem Cell Aging and Potentiate Anti‐Tumor Immunity |
| title_fullStr | Novel Arf1 Inhibitors Drive Cancer Stem Cell Aging and Potentiate Anti‐Tumor Immunity |
| title_full_unstemmed | Novel Arf1 Inhibitors Drive Cancer Stem Cell Aging and Potentiate Anti‐Tumor Immunity |
| title_short | Novel Arf1 Inhibitors Drive Cancer Stem Cell Aging and Potentiate Anti‐Tumor Immunity |
| title_sort | novel arf1 inhibitors drive cancer stem cell aging and potentiate anti tumor immunity |
| topic | anti‐tumor immunity Arf1 inhibitor cancer stem cell superior T cells trans‐cellular signaling |
| url | https://doi.org/10.1002/advs.202404442 |
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