A dual-targeting strategy to inhibit colorectal cancer liver metastasis via tumor cell ferroptosis and cancer-associated fibroblast reprogramming
Colorectal cancer (CRC) remains a leading cause of cancer‐related mortality, with liver metastasis posing a significant therapeutic challenge. Within the “seed and soil” paradigm, disrupting both tumor cells and their supportive microenvironment is essential to suppress disease progression. Here, we...
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KeAi Communications Co., Ltd.
2025-10-01
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2452199X25002191 |
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| author | Ziying Wu Xiewei Lin Yao Ying Gaowei Fan Junyao Shi Xiaoqing Zheng Ben Hu Hungchen Che Huiyang Chen Weilong Yang Xindi Fan Ke Mo Junming Wu Zhien Lan Zhiqiang Yu Shengtao Wang Chunhui Cui |
| author_facet | Ziying Wu Xiewei Lin Yao Ying Gaowei Fan Junyao Shi Xiaoqing Zheng Ben Hu Hungchen Che Huiyang Chen Weilong Yang Xindi Fan Ke Mo Junming Wu Zhien Lan Zhiqiang Yu Shengtao Wang Chunhui Cui |
| author_sort | Ziying Wu |
| collection | DOAJ |
| description | Colorectal cancer (CRC) remains a leading cause of cancer‐related mortality, with liver metastasis posing a significant therapeutic challenge. Within the “seed and soil” paradigm, disrupting both tumor cells and their supportive microenvironment is essential to suppress disease progression. Here, we utilized single‐cell transcriptomics of clinical CRC samples identified NOX4+ (NADPH oxidase 4 positive) cancer‐associated fibroblasts (CAFs) and CXCR4+ (C-X-C motif chemokine receptor 4 positive)/GPX4+ (glutathione peroxidase 4 positive) tumor cells as critical drivers of metastasis. Consequently, a dual‐targeted nanosystem was thus devised to induce ferroptosis in tumor cells and reprogram CAFs. This strategy integrates a ferroptosis inducer encapsulated within the cancer cell membrane and a CXCR4–NOX4 inhibitor loaded onto a hybrid membrane composed of cancer cells and CAFs, thereby achieving dual synergistic effects: ferroptotic eradication of malignant cells and induction of CAFs quiescence. In orthotopic, liver metastasis, and patient-derived tumor xenograft humanized immune mouse models, these nanoparticles significantly suppressed tumor growth, mitigated immunosuppressive signaling, and augmented antitumor immune responses, while maintaining favorable biocompatibility. These findings highlight the potential of simultaneously targeting ferroptosis in tumor cells and CAFs reprogramming in the tumor microenvironment to overcome liver metastasis of CRC. |
| format | Article |
| id | doaj-art-96a0b3fa9ce84ecfbf7a15109a05f721 |
| institution | Kabale University |
| issn | 2452-199X |
| language | English |
| publishDate | 2025-10-01 |
| publisher | KeAi Communications Co., Ltd. |
| record_format | Article |
| series | Bioactive Materials |
| spelling | doaj-art-96a0b3fa9ce84ecfbf7a15109a05f7212025-08-24T05:13:36ZengKeAi Communications Co., Ltd.Bioactive Materials2452-199X2025-10-0152739110.1016/j.bioactmat.2025.05.025A dual-targeting strategy to inhibit colorectal cancer liver metastasis via tumor cell ferroptosis and cancer-associated fibroblast reprogrammingZiying Wu0Xiewei Lin1Yao Ying2Gaowei Fan3Junyao Shi4Xiaoqing Zheng5Ben Hu6Hungchen Che7Huiyang Chen8Weilong Yang9Xindi Fan10Ke Mo11Junming Wu12Zhien Lan13Zhiqiang Yu14Shengtao Wang15Chunhui Cui16Department of General Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, ChinaDepartment of General Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, ChinaDepartment of General Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, ChinaDepartment of General Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, ChinaDepartment of General Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, ChinaThe First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, 510062, ChinaDepartment of General Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, ChinaDepartment of General Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, ChinaDepartment of Laboratory Medicine, Dongguan Institute of Clinical Cancer Research, The Tenth Affiliated Hospital of Southern Medical University (Dongguan people's hospital), Dongguan, 523018, ChinaDepartment of Laboratory Medicine, Dongguan Institute of Clinical Cancer Research, The Tenth Affiliated Hospital of Southern Medical University (Dongguan people's hospital), Dongguan, 523018, ChinaDepartment of General Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, ChinaDepartment of General Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, China; Department of Basic Science, YuanDong International Academy of Life Sciences, 999077, Hong Kong, ChinaDepartment of Basic Science, YuanDong International Academy of Life Sciences, 999077, Hong Kong, ChinaDepartment of General Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, ChinaDepartment of General Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, China; Department of Laboratory Medicine, Dongguan Institute of Clinical Cancer Research, The Tenth Affiliated Hospital of Southern Medical University (Dongguan people's hospital), Dongguan, 523018, China; Institute of Chemical Biology, Shenzhen Bay Laboratory, Shenzhen, 518132, China; Corresponding author. Department of General Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, China.Suzhou Institute for Advanced Research, University of Science and Technology of China, Suzhou, 215123, China; Corresponding author.Department of General Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, China; Corresponding author.Colorectal cancer (CRC) remains a leading cause of cancer‐related mortality, with liver metastasis posing a significant therapeutic challenge. Within the “seed and soil” paradigm, disrupting both tumor cells and their supportive microenvironment is essential to suppress disease progression. Here, we utilized single‐cell transcriptomics of clinical CRC samples identified NOX4+ (NADPH oxidase 4 positive) cancer‐associated fibroblasts (CAFs) and CXCR4+ (C-X-C motif chemokine receptor 4 positive)/GPX4+ (glutathione peroxidase 4 positive) tumor cells as critical drivers of metastasis. Consequently, a dual‐targeted nanosystem was thus devised to induce ferroptosis in tumor cells and reprogram CAFs. This strategy integrates a ferroptosis inducer encapsulated within the cancer cell membrane and a CXCR4–NOX4 inhibitor loaded onto a hybrid membrane composed of cancer cells and CAFs, thereby achieving dual synergistic effects: ferroptotic eradication of malignant cells and induction of CAFs quiescence. In orthotopic, liver metastasis, and patient-derived tumor xenograft humanized immune mouse models, these nanoparticles significantly suppressed tumor growth, mitigated immunosuppressive signaling, and augmented antitumor immune responses, while maintaining favorable biocompatibility. These findings highlight the potential of simultaneously targeting ferroptosis in tumor cells and CAFs reprogramming in the tumor microenvironment to overcome liver metastasis of CRC.http://www.sciencedirect.com/science/article/pii/S2452199X25002191Colorectal cancer liver metastasisFerroptosisCancer-associated fibroblastsTumor microenvironmentDual-targeted nanosystem |
| spellingShingle | Ziying Wu Xiewei Lin Yao Ying Gaowei Fan Junyao Shi Xiaoqing Zheng Ben Hu Hungchen Che Huiyang Chen Weilong Yang Xindi Fan Ke Mo Junming Wu Zhien Lan Zhiqiang Yu Shengtao Wang Chunhui Cui A dual-targeting strategy to inhibit colorectal cancer liver metastasis via tumor cell ferroptosis and cancer-associated fibroblast reprogramming Bioactive Materials Colorectal cancer liver metastasis Ferroptosis Cancer-associated fibroblasts Tumor microenvironment Dual-targeted nanosystem |
| title | A dual-targeting strategy to inhibit colorectal cancer liver metastasis via tumor cell ferroptosis and cancer-associated fibroblast reprogramming |
| title_full | A dual-targeting strategy to inhibit colorectal cancer liver metastasis via tumor cell ferroptosis and cancer-associated fibroblast reprogramming |
| title_fullStr | A dual-targeting strategy to inhibit colorectal cancer liver metastasis via tumor cell ferroptosis and cancer-associated fibroblast reprogramming |
| title_full_unstemmed | A dual-targeting strategy to inhibit colorectal cancer liver metastasis via tumor cell ferroptosis and cancer-associated fibroblast reprogramming |
| title_short | A dual-targeting strategy to inhibit colorectal cancer liver metastasis via tumor cell ferroptosis and cancer-associated fibroblast reprogramming |
| title_sort | dual targeting strategy to inhibit colorectal cancer liver metastasis via tumor cell ferroptosis and cancer associated fibroblast reprogramming |
| topic | Colorectal cancer liver metastasis Ferroptosis Cancer-associated fibroblasts Tumor microenvironment Dual-targeted nanosystem |
| url | http://www.sciencedirect.com/science/article/pii/S2452199X25002191 |
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