Reprogramming tumor-associated macrophages and blocking PD-L1 via engineered outer membrane vesicles to enhance T cell infiltration and cytotoxic functions
Abstract The immunosuppressive tumor microenvironment (TME) critically undermines the efficacy of T cell-based tumor immunotherapy by impeding CD8+ T cell infiltration and cytotoxic function, primarily through tumor-associated macrophages (TAMs) and immune checkpoint molecules such as programmed dea...
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| Format: | Article |
| 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/s12951-025-03507-7 |
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| author | Zhiqiang Chen Bo Wang Jianwei Zheng Chao Liu Peijun Xu Qianqian Zhou Jiayong Li Zijian Shi Zhenduo Wang Xuyan Wang Shunjin Xia Fangquan Xu Xiaofeng Yao Yu Wang Xinwei Wang Xiao Zhao Nana Ma Yu Ren Keman Cheng Xuan Zhou |
| author_facet | Zhiqiang Chen Bo Wang Jianwei Zheng Chao Liu Peijun Xu Qianqian Zhou Jiayong Li Zijian Shi Zhenduo Wang Xuyan Wang Shunjin Xia Fangquan Xu Xiaofeng Yao Yu Wang Xinwei Wang Xiao Zhao Nana Ma Yu Ren Keman Cheng Xuan Zhou |
| author_sort | Zhiqiang Chen |
| collection | DOAJ |
| description | Abstract The immunosuppressive tumor microenvironment (TME) critically undermines the efficacy of T cell-based tumor immunotherapy by impeding CD8+ T cell infiltration and cytotoxic function, primarily through tumor-associated macrophages (TAMs) and immune checkpoint molecules such as programmed death ligand 1 (PD-L1). Here, we present a multifunctional nanoplatform, IN@OMV-PDL1nb, designed to simultaneously inhibit TAM-derived immunosuppressive metabolite itaconic acid (ITA) by targeting immune-responsive gene 1 (IRG1) and block PD-L1 within the TME. Engineered outer membrane vesicles (OMVs) serve as precision delivery vehicles for the IRG1 inhibitor IRG1-IN-1 (IN) and as carriers for PD-L1 nanobody release, activated by matrix metalloproteinase-2 (MMP-2). IN@OMV-PDL1nb effectively inhibits IRG1 expression in TAMs, thus reducing the accumulation of ITA, restoring chemokines (CXCL9 and CXCL10) secretion, and enhancing CD8+ T cells infiltration within tumors. The released PD-L1 nanobody protects CD8+ T cells, preserving their tumoricidal activity. In murine tumor models, IN@OMV-PDL1nb significantly inhibited tumor growth, increased survival, and enhanced antigen presentation and T cell recruitment. Additionally, IN@OMV-PDL1nb induced robust adaptive immunity, facilitating antigen-specific immune memory that prevented tumor recurrence and metastasis. This dual-targeting approach offers a promising strategy to overcome TME-driven immunosuppression in tumor immunotherapy. |
| format | Article |
| id | doaj-art-38e0159e93454262a87b020b4e0127d0 |
| institution | Kabale University |
| issn | 1477-3155 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Nanobiotechnology |
| spelling | doaj-art-38e0159e93454262a87b020b4e0127d02025-08-20T03:46:24ZengBMCJournal of Nanobiotechnology1477-31552025-07-0123112110.1186/s12951-025-03507-7Reprogramming tumor-associated macrophages and blocking PD-L1 via engineered outer membrane vesicles to enhance T cell infiltration and cytotoxic functionsZhiqiang Chen0Bo Wang1Jianwei Zheng2Chao Liu3Peijun Xu4Qianqian Zhou5Jiayong Li6Zijian Shi7Zhenduo Wang8Xuyan Wang9Shunjin Xia10Fangquan Xu11Xiaofeng Yao12Yu Wang13Xinwei Wang14Xiao Zhao15Nana Ma16Yu Ren17Keman Cheng18Xuan Zhou19Department of Maxillofacial and Otorhinolaryngological Oncology, Tianjin Medical University Cancer Institute & Hospital, Key Laboratory of Basic and Translational Medicine on Head & Neck Cancer, National Clinical Research Center for Cancer, Tianjin’s Clinical Research Center for Cancer, State Key Laboratory of Druggability Evaluation and Systematic Translational MedicineDepartment of Maxillofacial and Otorhinolaryngological Oncology, Tianjin Medical University Cancer Institute & Hospital, Key Laboratory of Basic and Translational Medicine on Head & Neck Cancer, National Clinical Research Center for Cancer, Tianjin’s Clinical Research Center for Cancer, State Key Laboratory of Druggability Evaluation and Systematic Translational MedicineDepartment of Cell Biology, School of Basic Medical Sciences, Tianjin Medical UniversityDepartment of Maxillofacial and Otorhinolaryngological Oncology, Tianjin Medical University Cancer Institute & Hospital, Key Laboratory of Basic and Translational Medicine on Head & Neck Cancer, National Clinical Research Center for Cancer, Tianjin’s Clinical Research Center for Cancer, State Key Laboratory of Druggability Evaluation and Systematic Translational MedicineCAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and TechnologyDepartment of Maxillofacial and Otorhinolaryngological Oncology, Tianjin Medical University Cancer Institute & Hospital, Key Laboratory of Basic and Translational Medicine on Head & Neck Cancer, National Clinical Research Center for Cancer, Tianjin’s Clinical Research Center for Cancer, State Key Laboratory of Druggability Evaluation and Systematic Translational MedicineDepartment of Maxillofacial and Otorhinolaryngological Oncology, Tianjin Medical University Cancer Institute & Hospital, Key Laboratory of Basic and Translational Medicine on Head & Neck Cancer, National Clinical Research Center for Cancer, Tianjin’s Clinical Research Center for Cancer, State Key Laboratory of Druggability Evaluation and Systematic Translational MedicineDepartment of Maxillofacial and Otorhinolaryngological Oncology, Tianjin Medical University Cancer Institute & Hospital, Key Laboratory of Basic and Translational Medicine on Head & Neck Cancer, National Clinical Research Center for Cancer, Tianjin’s Clinical Research Center for Cancer, State Key Laboratory of Druggability Evaluation and Systematic Translational MedicineDepartment of Maxillofacial and Otorhinolaryngological Oncology, Tianjin Medical University Cancer Institute & Hospital, Key Laboratory of Basic and Translational Medicine on Head & Neck Cancer, National Clinical Research Center for Cancer, Tianjin’s Clinical Research Center for Cancer, State Key Laboratory of Druggability Evaluation and Systematic Translational MedicineDepartment of Maxillofacial and Otorhinolaryngological Oncology, Tianjin Medical University Cancer Institute & Hospital, Key Laboratory of Basic and Translational Medicine on Head & Neck Cancer, National Clinical Research Center for Cancer, Tianjin’s Clinical Research Center for Cancer, State Key Laboratory of Druggability Evaluation and Systematic Translational MedicineDepartment of Maxillofacial and Otorhinolaryngological Oncology, Tianjin Medical University Cancer Institute & Hospital, Key Laboratory of Basic and Translational Medicine on Head & Neck Cancer, National Clinical Research Center for Cancer, Tianjin’s Clinical Research Center for Cancer, State Key Laboratory of Druggability Evaluation and Systematic Translational MedicineDepartment of Maxillofacial and Otorhinolaryngological Oncology, Tianjin Medical University Cancer Institute & Hospital, Key Laboratory of Basic and Translational Medicine on Head & Neck Cancer, National Clinical Research Center for Cancer, Tianjin’s Clinical Research Center for Cancer, State Key Laboratory of Druggability Evaluation and Systematic Translational MedicineDepartment of Maxillofacial and Otorhinolaryngological Oncology, Tianjin Medical University Cancer Institute & Hospital, Key Laboratory of Basic and Translational Medicine on Head & Neck Cancer, National Clinical Research Center for Cancer, Tianjin’s Clinical Research Center for Cancer, State Key Laboratory of Druggability Evaluation and Systematic Translational MedicineDepartment of Maxillofacial and Otorhinolaryngological Oncology, Tianjin Medical University Cancer Institute & Hospital, Key Laboratory of Basic and Translational Medicine on Head & Neck Cancer, National Clinical Research Center for Cancer, Tianjin’s Clinical Research Center for Cancer, State Key Laboratory of Druggability Evaluation and Systematic Translational MedicineCAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and TechnologyCAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and TechnologyInstitute of Biophysics, Chinese Academy of SciencesDepartment of Genetics, School of Basic Medical Sciences, Tianjin Medical UniversityCAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and TechnologyDepartment of Maxillofacial and Otorhinolaryngological Oncology, Tianjin Medical University Cancer Institute & Hospital, Key Laboratory of Basic and Translational Medicine on Head & Neck Cancer, National Clinical Research Center for Cancer, Tianjin’s Clinical Research Center for Cancer, State Key Laboratory of Druggability Evaluation and Systematic Translational MedicineAbstract The immunosuppressive tumor microenvironment (TME) critically undermines the efficacy of T cell-based tumor immunotherapy by impeding CD8+ T cell infiltration and cytotoxic function, primarily through tumor-associated macrophages (TAMs) and immune checkpoint molecules such as programmed death ligand 1 (PD-L1). Here, we present a multifunctional nanoplatform, IN@OMV-PDL1nb, designed to simultaneously inhibit TAM-derived immunosuppressive metabolite itaconic acid (ITA) by targeting immune-responsive gene 1 (IRG1) and block PD-L1 within the TME. Engineered outer membrane vesicles (OMVs) serve as precision delivery vehicles for the IRG1 inhibitor IRG1-IN-1 (IN) and as carriers for PD-L1 nanobody release, activated by matrix metalloproteinase-2 (MMP-2). IN@OMV-PDL1nb effectively inhibits IRG1 expression in TAMs, thus reducing the accumulation of ITA, restoring chemokines (CXCL9 and CXCL10) secretion, and enhancing CD8+ T cells infiltration within tumors. The released PD-L1 nanobody protects CD8+ T cells, preserving their tumoricidal activity. In murine tumor models, IN@OMV-PDL1nb significantly inhibited tumor growth, increased survival, and enhanced antigen presentation and T cell recruitment. Additionally, IN@OMV-PDL1nb induced robust adaptive immunity, facilitating antigen-specific immune memory that prevented tumor recurrence and metastasis. This dual-targeting approach offers a promising strategy to overcome TME-driven immunosuppression in tumor immunotherapy.https://doi.org/10.1186/s12951-025-03507-7Tumor immunotherapyTumor microenvironmentImmune checkpoint blockadeTumor-associated macrophagesOuter membrane vesicles |
| spellingShingle | Zhiqiang Chen Bo Wang Jianwei Zheng Chao Liu Peijun Xu Qianqian Zhou Jiayong Li Zijian Shi Zhenduo Wang Xuyan Wang Shunjin Xia Fangquan Xu Xiaofeng Yao Yu Wang Xinwei Wang Xiao Zhao Nana Ma Yu Ren Keman Cheng Xuan Zhou Reprogramming tumor-associated macrophages and blocking PD-L1 via engineered outer membrane vesicles to enhance T cell infiltration and cytotoxic functions Journal of Nanobiotechnology Tumor immunotherapy Tumor microenvironment Immune checkpoint blockade Tumor-associated macrophages Outer membrane vesicles |
| title | Reprogramming tumor-associated macrophages and blocking PD-L1 via engineered outer membrane vesicles to enhance T cell infiltration and cytotoxic functions |
| title_full | Reprogramming tumor-associated macrophages and blocking PD-L1 via engineered outer membrane vesicles to enhance T cell infiltration and cytotoxic functions |
| title_fullStr | Reprogramming tumor-associated macrophages and blocking PD-L1 via engineered outer membrane vesicles to enhance T cell infiltration and cytotoxic functions |
| title_full_unstemmed | Reprogramming tumor-associated macrophages and blocking PD-L1 via engineered outer membrane vesicles to enhance T cell infiltration and cytotoxic functions |
| title_short | Reprogramming tumor-associated macrophages and blocking PD-L1 via engineered outer membrane vesicles to enhance T cell infiltration and cytotoxic functions |
| title_sort | reprogramming tumor associated macrophages and blocking pd l1 via engineered outer membrane vesicles to enhance t cell infiltration and cytotoxic functions |
| topic | Tumor immunotherapy Tumor microenvironment Immune checkpoint blockade Tumor-associated macrophages Outer membrane vesicles |
| url | https://doi.org/10.1186/s12951-025-03507-7 |
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