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<p>The immunosuppressive tumor microenvironment (TME) critically undermines the efficacy of T cell-based tumor immunotherapy by impeding CD8<sup>+</sup> 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<sup>+</sup> T cells infiltration within tumors. The released PD-L1 nanobody protects CD8<sup>+</sup> 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年7月15日

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  • 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

摘要

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.