CXCL12-targeting siRNA nanoparticles alleviate immunosuppression and inhibit tumor progression in esophageal squamous cell carcinoma
Abstract Esophageal squamous cell carcinoma (ESCC) is associated with a highly immunosuppressive tumor microenvironment (TME), driven in part by cancer-associated fibroblasts (CAFs) that promote immune evasion through the secretion of CXCL12. CXCL12 interacts with the CXCR4 receptor on immune cells,...
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| Language: | English |
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BMC
2025-07-01
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| Series: | Journal of Nanobiotechnology |
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| Online Access: | https://doi.org/10.1186/s12951-025-03476-x |
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| author | Shuyao Zhang Hong Jiang Chengkuan Zhao Yanli Lei Shaojie Liu Chengcheng Xu Xiaoshan Chen Danling Zheng Xiaolong Wu Xinyue Lin Wang Chen Yun Chen Jianxiang Huang XiaoLong Wei Yihui Huang Chaoxian Lin |
| author_facet | Shuyao Zhang Hong Jiang Chengkuan Zhao Yanli Lei Shaojie Liu Chengcheng Xu Xiaoshan Chen Danling Zheng Xiaolong Wu Xinyue Lin Wang Chen Yun Chen Jianxiang Huang XiaoLong Wei Yihui Huang Chaoxian Lin |
| author_sort | Shuyao Zhang |
| collection | DOAJ |
| description | Abstract Esophageal squamous cell carcinoma (ESCC) is associated with a highly immunosuppressive tumor microenvironment (TME), driven in part by cancer-associated fibroblasts (CAFs) that promote immune evasion through the secretion of CXCL12. CXCL12 interacts with the CXCR4 receptor on immune cells, disrupting CD8+ T cell migration and anti-tumor function. To address this, we developed an innovative siRNA-based therapeutic approach targeting CXCL12 in CAFs. Using lipid nanocarriers (LNCs) as delivery vehicles, we engineered LNCs@si-CXCL12 nanoparticles to specifically silence CXCL12 expression in CAFs. In vitro studies demonstrated that LNCs@si-CXCL12 restored CD8+ T cell migration and inhibited ESCC cell proliferation and migration. In vivo experiments in a spontaneous ESCC mouse model showed that CXCL12 silencing through nanoparticle delivery significantly reduced tumor growth, enhanced CD8+ T cell-mediated tumoricidal activity, and improved overall survival. These findings highlight the potential of siRNA-loaded nanoparticles targeting CXCL12 as a novel therapeutic strategy to reprogram the immunosuppressive TME and enhance immune responses in ESCC. This approach provides a promising avenue for improving treatment outcomes and overcoming immune evasion in ESCC. Graphical abstract |
| format | Article |
| id | doaj-art-0c6e103aca1547ab9d0e7e0b41a3d033 |
| institution | Kabale University |
| issn | 1477-3155 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Nanobiotechnology |
| spelling | doaj-art-0c6e103aca1547ab9d0e7e0b41a3d0332025-08-20T04:03:07ZengBMCJournal of Nanobiotechnology1477-31552025-07-0123112710.1186/s12951-025-03476-xCXCL12-targeting siRNA nanoparticles alleviate immunosuppression and inhibit tumor progression in esophageal squamous cell carcinomaShuyao Zhang0Hong Jiang1Chengkuan Zhao2Yanli Lei3Shaojie Liu4Chengcheng Xu5Xiaoshan Chen6Danling Zheng7Xiaolong Wu8Xinyue Lin9Wang Chen10Yun Chen11Jianxiang Huang12XiaoLong Wei13Yihui Huang14Chaoxian Lin15Department of Pharmacy, Guangzhou Red Cross Hospital of Jinan UniversityDepartment of Nursing, Guangzhou Red Cross Hospital of Jinan UniversityCollege of Pharmacy, Jinan UniversityDepartment of Pharmacy, The 2nd, People’s Hospital of BijieDepartment of Gastrointestinal Surgery, Guangzhou Red Cross Hospital of Jinan UniversityDepartment of Pharmacy, Guangzhou Red Cross Hospital of Jinan UniversityDepartment of Pharmacy, Guangzhou Red Cross Hospital of Jinan UniversityDepartment of Pharmacy, Guangzhou Red Cross Hospital of Jinan UniversityCollege of Pharmacy, Jinan UniversityDepartment of Pharmacology, Shantou University Medical CollegeDepartment of Pharmacy, Guangzhou Red Cross Hospital of Jinan UniversityDepartment of Pharmacy, Guangzhou Red Cross Hospital of Jinan UniversityCollege of Pharmacy, Jinan UniversityDepartment of Pathology, Cancer Hospital of Shantou University Medical CollegeDepartment of Pediatrics, Guangzhou Red Cross Hospital of Jinan UniversityDepartment of Pharmacology, Shantou University Medical CollegeAbstract Esophageal squamous cell carcinoma (ESCC) is associated with a highly immunosuppressive tumor microenvironment (TME), driven in part by cancer-associated fibroblasts (CAFs) that promote immune evasion through the secretion of CXCL12. CXCL12 interacts with the CXCR4 receptor on immune cells, disrupting CD8+ T cell migration and anti-tumor function. To address this, we developed an innovative siRNA-based therapeutic approach targeting CXCL12 in CAFs. Using lipid nanocarriers (LNCs) as delivery vehicles, we engineered LNCs@si-CXCL12 nanoparticles to specifically silence CXCL12 expression in CAFs. In vitro studies demonstrated that LNCs@si-CXCL12 restored CD8+ T cell migration and inhibited ESCC cell proliferation and migration. In vivo experiments in a spontaneous ESCC mouse model showed that CXCL12 silencing through nanoparticle delivery significantly reduced tumor growth, enhanced CD8+ T cell-mediated tumoricidal activity, and improved overall survival. These findings highlight the potential of siRNA-loaded nanoparticles targeting CXCL12 as a novel therapeutic strategy to reprogram the immunosuppressive TME and enhance immune responses in ESCC. This approach provides a promising avenue for improving treatment outcomes and overcoming immune evasion in ESCC. Graphical abstracthttps://doi.org/10.1186/s12951-025-03476-xEsophageal squamous cell carcinomaTumor microenvironmentCancer-associated fibroblastsCXCL12SiRNA nanoparticles |
| spellingShingle | Shuyao Zhang Hong Jiang Chengkuan Zhao Yanli Lei Shaojie Liu Chengcheng Xu Xiaoshan Chen Danling Zheng Xiaolong Wu Xinyue Lin Wang Chen Yun Chen Jianxiang Huang XiaoLong Wei Yihui Huang Chaoxian Lin CXCL12-targeting siRNA nanoparticles alleviate immunosuppression and inhibit tumor progression in esophageal squamous cell carcinoma Journal of Nanobiotechnology Esophageal squamous cell carcinoma Tumor microenvironment Cancer-associated fibroblasts CXCL12 SiRNA nanoparticles |
| title | CXCL12-targeting siRNA nanoparticles alleviate immunosuppression and inhibit tumor progression in esophageal squamous cell carcinoma |
| title_full | CXCL12-targeting siRNA nanoparticles alleviate immunosuppression and inhibit tumor progression in esophageal squamous cell carcinoma |
| title_fullStr | CXCL12-targeting siRNA nanoparticles alleviate immunosuppression and inhibit tumor progression in esophageal squamous cell carcinoma |
| title_full_unstemmed | CXCL12-targeting siRNA nanoparticles alleviate immunosuppression and inhibit tumor progression in esophageal squamous cell carcinoma |
| title_short | CXCL12-targeting siRNA nanoparticles alleviate immunosuppression and inhibit tumor progression in esophageal squamous cell carcinoma |
| title_sort | cxcl12 targeting sirna nanoparticles alleviate immunosuppression and inhibit tumor progression in esophageal squamous cell carcinoma |
| topic | Esophageal squamous cell carcinoma Tumor microenvironment Cancer-associated fibroblasts CXCL12 SiRNA nanoparticles |
| url | https://doi.org/10.1186/s12951-025-03476-x |
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