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  3. Reprogramming tumor-associated macrophages and blocking PD-L1 via engineered outer membrane vesicles to enhance T cell infiltration and cytotoxic functions

Reprogramming tumor-associated macrophages and blocking PD-L1 via engineered outer membrane vesicles to enhance T cell infiltration and cytotoxic functions

  • J Nanobiotechnology. 2025 Jul 15;23(1):514. doi: 10.1186/s12951-025-03507-7.
Zhiqiang Chen # 1 2,  Bo Wang # 1,  Jianwei Zheng # 3,  Chao Liu 1,  Peijun Xu 2,  Qianqian Zhou 1,  Jiayong Li 1,  Zijian Shi 1,  Zhenduo Wang 1,  Xuyan Wang 1,  Shunjin Xia 1,  Fangquan Xu 1,  Xiaofeng Yao 1,  Yu Wang 1,  Xinwei Wang 2,  Xiao Zhao 2,  Nana Ma 4,  Yu Ren 5,  Keman Cheng 6,  Xuan Zhou 7
Affiliations

Affiliations

  • 1 Department 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 Medicine, Tianjin, 300060, China.
  • 2 CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, No.11 Zhongguancun Beiyitiao, Beijing, 100190, China.
  • 3 Department of Cell Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, 300070, China.
  • 4 Institute of Biophysics, Chinese Academy of Sciences, Beijing, China. nanama@ibp.ac.cn.
  • 5 Department of Genetics, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, 300070, China. yuren0925@tmu.edu.cn.
  • 6 CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, No.11 Zhongguancun Beiyitiao, Beijing, 100190, China. chengkm@nanoctr.cn.
  • 7 Department 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 Medicine, Tianjin, 300060, China. xuanzhou@tmu.edu.cn.
  • # Contributed equally.
PMID: 40660251 DOI: 10.1186/s12951-025-03507-7
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.

Keywords

Immune checkpoint blockade; Outer membrane vesicles; Tumor immunotherapy; Tumor microenvironment; Tumor-associated macrophages.

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