Zonated Copper‐Driven Breast Cancer Progression Countered by a Copper‐Depleting Nanoagent for Immune and Metabolic Reprogramming
Abstract While studies of various carcinomas have reported aberrant metal metabolism, much remains unknown regarding their spatial accumulation and regulatory impacts in tumors. Here, elevated copper levels are detected in breast cancer tumors from patients and animal models, specifically exhibiting...
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Wiley
2025-05-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202412434 |
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| author | Lin Chen Saibo Ma Hao Wu Lingna Zheng Yunpeng Yi Guangnian Liu Baoyi Li Jiayi Sun Yang Du Bing Wang Yike Liu Cheng Zhang Jing Chang Yuheng Pang Wenjing Wang Meng Wang Motao Zhu |
| author_facet | Lin Chen Saibo Ma Hao Wu Lingna Zheng Yunpeng Yi Guangnian Liu Baoyi Li Jiayi Sun Yang Du Bing Wang Yike Liu Cheng Zhang Jing Chang Yuheng Pang Wenjing Wang Meng Wang Motao Zhu |
| author_sort | Lin Chen |
| collection | DOAJ |
| description | Abstract While studies of various carcinomas have reported aberrant metal metabolism, much remains unknown regarding their spatial accumulation and regulatory impacts in tumors. Here, elevated copper levels are detected in breast cancer tumors from patients and animal models, specifically exhibiting a zonate spatial pattern. Spatially resolved multiomics analyses reveal that copper zonation drives a tumor metabolic preference for oxidative phosphorylation (OXPHOS) over glycolysis and promotes tumor metastatic and immune‐desert phenotypes. Then, a copper‐depleting nanoagent is developed based on copper chelator tetrathiomolybdate (TM)‐loaded hybridized bacterial outer membrane vesicles (hOMVs) from both Akkermansia muciniphila bacteria and CD326‐targeting peptide‐engineered Escherichia coli (TM@CD326hOMV). Systemic administration of TM@CD326hOMV reduces the labile copper level in tumors and inhibits both tumor growth and metastatic phenotypes, specifically through metabolic reprograming of OXPHOS toward glycolysis and restoration of antitumor immunity responses involving natural killer cells, CD4+ T cells, and cytotoxic CD8+ T cells in tumors. Assessing survival in murine breast cancer models, a combination of TM@CD326hOMV and a checkpoint blockade agent outperforms monotherapies. Notably, a copper‐rich diet undermines the therapeutic efficacy of TM@CD326hOMV. Beyond demonstrating an effective nanoagent for treating breast cancer, this study deepens the understanding of how the pattern of copper accumulation in tumors affects pathophysiology and immunity. |
| format | Article |
| id | doaj-art-07c5035d8d0342b58d95f133d4ce1c71 |
| institution | OA Journals |
| issn | 2198-3844 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj-art-07c5035d8d0342b58d95f133d4ce1c712025-08-20T02:02:16ZengWileyAdvanced Science2198-38442025-05-011220n/an/a10.1002/advs.202412434Zonated Copper‐Driven Breast Cancer Progression Countered by a Copper‐Depleting Nanoagent for Immune and Metabolic ReprogrammingLin Chen0Saibo Ma1Hao Wu2Lingna Zheng3Yunpeng Yi4Guangnian Liu5Baoyi Li6Jiayi Sun7Yang Du8Bing Wang9Yike Liu10Cheng Zhang11Jing Chang12Yuheng Pang13Wenjing Wang14Meng Wang15Motao Zhu16CAS Key Laboratory for Biomedical Effects of Nanomaterials & Nanosafety CAS Center for Excellence in Nanoscience National Center for Nanoscience and Technology Beijing 100190 ChinaCAS Key Laboratory for Biomedical Effects of Nanomaterials & Nanosafety CAS Center for Excellence in Nanoscience National Center for Nanoscience and Technology Beijing 100190 ChinaCAS Key Laboratory for Biomedical Effects of Nanomaterials & Nanosafety CAS Center for Excellence in Nanoscience National Center for Nanoscience and Technology Beijing 100190 ChinaKey Laboratory of Nuclear Analytical Techniques and Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety Institute of High Energy Physics Chinese Academy of Sciences Beijing 100049 ChinaShandong Provincial Animal and Poultry Green Health Products Creation Engineering Laboratory Institute of Poultry Science Shandong Academy of Agricultural Science Jinan 250100 ChinaCAS Key Laboratory for Biomedical Effects of Nanomaterials & Nanosafety CAS Center for Excellence in Nanoscience National Center for Nanoscience and Technology Beijing 100190 ChinaCAS Key Laboratory for Biomedical Effects of Nanomaterials & Nanosafety CAS Center for Excellence in Nanoscience National Center for Nanoscience and Technology Beijing 100190 ChinaCAS Key Laboratory for Biomedical Effects of Nanomaterials & Nanosafety CAS Center for Excellence in Nanoscience National Center for Nanoscience and Technology Beijing 100190 ChinaCAS Key Laboratory for Biomedical Effects of Nanomaterials & Nanosafety CAS Center for Excellence in Nanoscience National Center for Nanoscience and Technology Beijing 100190 ChinaKey Laboratory of Nuclear Analytical Techniques and Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety Institute of High Energy Physics Chinese Academy of Sciences Beijing 100049 ChinaCAS Key Laboratory for Biomedical Effects of Nanomaterials & Nanosafety CAS Center for Excellence in Nanoscience National Center for Nanoscience and Technology Beijing 100190 ChinaState Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers Beijing Key Laboratory of Carcinogenesis and Translational Research Department of Gastrointestinal Oncology Peking University Cancer Hospital & Institute Beijing 100142 ChinaCollege of Marine Life Science Ocean University of China Qingdao 266003 ChinaBeijing YouAn Hospital Capital Medical University Beijing Institute of Hepatology Beijing 100069 ChinaBeijing YouAn Hospital Capital Medical University Beijing Institute of Hepatology Beijing 100069 ChinaKey Laboratory of Nuclear Analytical Techniques and Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety Institute of High Energy Physics Chinese Academy of Sciences Beijing 100049 ChinaCAS Key Laboratory for Biomedical Effects of Nanomaterials & Nanosafety CAS Center for Excellence in Nanoscience National Center for Nanoscience and Technology Beijing 100190 ChinaAbstract While studies of various carcinomas have reported aberrant metal metabolism, much remains unknown regarding their spatial accumulation and regulatory impacts in tumors. Here, elevated copper levels are detected in breast cancer tumors from patients and animal models, specifically exhibiting a zonate spatial pattern. Spatially resolved multiomics analyses reveal that copper zonation drives a tumor metabolic preference for oxidative phosphorylation (OXPHOS) over glycolysis and promotes tumor metastatic and immune‐desert phenotypes. Then, a copper‐depleting nanoagent is developed based on copper chelator tetrathiomolybdate (TM)‐loaded hybridized bacterial outer membrane vesicles (hOMVs) from both Akkermansia muciniphila bacteria and CD326‐targeting peptide‐engineered Escherichia coli (TM@CD326hOMV). Systemic administration of TM@CD326hOMV reduces the labile copper level in tumors and inhibits both tumor growth and metastatic phenotypes, specifically through metabolic reprograming of OXPHOS toward glycolysis and restoration of antitumor immunity responses involving natural killer cells, CD4+ T cells, and cytotoxic CD8+ T cells in tumors. Assessing survival in murine breast cancer models, a combination of TM@CD326hOMV and a checkpoint blockade agent outperforms monotherapies. Notably, a copper‐rich diet undermines the therapeutic efficacy of TM@CD326hOMV. Beyond demonstrating an effective nanoagent for treating breast cancer, this study deepens the understanding of how the pattern of copper accumulation in tumors affects pathophysiology and immunity.https://doi.org/10.1002/advs.202412434Akkermansia muciniphilabreast cancercoppermetabolic reprogrammingouter membrane vesiclesspatially resolved multiomics |
| spellingShingle | Lin Chen Saibo Ma Hao Wu Lingna Zheng Yunpeng Yi Guangnian Liu Baoyi Li Jiayi Sun Yang Du Bing Wang Yike Liu Cheng Zhang Jing Chang Yuheng Pang Wenjing Wang Meng Wang Motao Zhu Zonated Copper‐Driven Breast Cancer Progression Countered by a Copper‐Depleting Nanoagent for Immune and Metabolic Reprogramming Advanced Science Akkermansia muciniphila breast cancer copper metabolic reprogramming outer membrane vesicles spatially resolved multiomics |
| title | Zonated Copper‐Driven Breast Cancer Progression Countered by a Copper‐Depleting Nanoagent for Immune and Metabolic Reprogramming |
| title_full | Zonated Copper‐Driven Breast Cancer Progression Countered by a Copper‐Depleting Nanoagent for Immune and Metabolic Reprogramming |
| title_fullStr | Zonated Copper‐Driven Breast Cancer Progression Countered by a Copper‐Depleting Nanoagent for Immune and Metabolic Reprogramming |
| title_full_unstemmed | Zonated Copper‐Driven Breast Cancer Progression Countered by a Copper‐Depleting Nanoagent for Immune and Metabolic Reprogramming |
| title_short | Zonated Copper‐Driven Breast Cancer Progression Countered by a Copper‐Depleting Nanoagent for Immune and Metabolic Reprogramming |
| title_sort | zonated copper driven breast cancer progression countered by a copper depleting nanoagent for immune and metabolic reprogramming |
| topic | Akkermansia muciniphila breast cancer copper metabolic reprogramming outer membrane vesicles spatially resolved multiomics |
| url | https://doi.org/10.1002/advs.202412434 |
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