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Background <p>Dendritic cell-derived exosomes (DEXs) are emerging as effective platforms for cancer vaccines due to their capacity to present tumor antigens and regulate immune responses. Here, we developed a multifunctional DEX vaccine (DEX<sub>AGNP</sub>) that integrates liver cancer epitope presentation, innate immune activation, and checkpoint modulation. Human DEX<sub>AGNP</sub> was generated by loading HLA-A*02:01-restricted hAFP<sub>158-166</sub> and hGPC3<sub>144-152</sub> peptides, and murine DEX<sub>AGNP</sub> by loading mAFP<sub>212-219</sub> and mGPC3<sub>127-136</sub> peptides. The N-terminal functional domain of high-mobility group nucleosome-binding protein 1 (N1ND) was membrane-anchored via CHOL-PEG2000, and programmed death ligand 1 (PD-L1) of DEXs surface was blocked with anti-PD-L1 antibodies to mitigate immunosuppression.</p> Results <p>DEX<sub>AGNP</sub> vaccine enhanced antigen-specific CD8⁺ T-cell responses, as supported by peptide-MHC tetramer staining, and promoted cytokine-associated effector activity. In vitro, DEX<sub>AGNP</sub>-primed T cells mediated cytotoxicity against both human and murine liver cancer cell lines. In vivo, DEX<sub>AGNP</sub> suppressed tumor growth in an immunocompetent subcutaneous H22 model and a humanized HepG2 xenograft model, and demonstrated antitumor activity in an orthotopic HCC model. In addition, DEX<sub>AGNP</sub> induced measurable killing in ex vivo assays using clinical HCC specimens and, in the prophylactic setting, was associated with enhanced memory-like T-cell responses.</p> Conclusion <p>DEX<sub>AGNP</sub> is a modular exosome vaccine that combines epitope-specific antigen presentation with immune activation and PD-L1 blockade, enabling robust antitumor T-cell responses across complementary liver cancer models. This engineered DEX platform provides a practical blueprint for developing next-generation exosome-based cancer vaccines.</p> Graphical abstract <p></p>

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Immune-modified exosome vaccine loaded with liver cancer epitope peptides induces potent and specific antitumor immunity

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月24日

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  • Shumin Luo,
  • Li Xiao,
  • Fang Xu,
  • Pengpeng Lu,
  • Yiyue Wang,
  • Chuanyun Li,
  • Enhong Xing,
  • Weihua Li

摘要

Background

Dendritic cell-derived exosomes (DEXs) are emerging as effective platforms for cancer vaccines due to their capacity to present tumor antigens and regulate immune responses. Here, we developed a multifunctional DEX vaccine (DEXAGNP) that integrates liver cancer epitope presentation, innate immune activation, and checkpoint modulation. Human DEXAGNP was generated by loading HLA-A*02:01-restricted hAFP158-166 and hGPC3144-152 peptides, and murine DEXAGNP by loading mAFP212-219 and mGPC3127-136 peptides. The N-terminal functional domain of high-mobility group nucleosome-binding protein 1 (N1ND) was membrane-anchored via CHOL-PEG2000, and programmed death ligand 1 (PD-L1) of DEXs surface was blocked with anti-PD-L1 antibodies to mitigate immunosuppression.

Results

DEXAGNP vaccine enhanced antigen-specific CD8⁺ T-cell responses, as supported by peptide-MHC tetramer staining, and promoted cytokine-associated effector activity. In vitro, DEXAGNP-primed T cells mediated cytotoxicity against both human and murine liver cancer cell lines. In vivo, DEXAGNP suppressed tumor growth in an immunocompetent subcutaneous H22 model and a humanized HepG2 xenograft model, and demonstrated antitumor activity in an orthotopic HCC model. In addition, DEXAGNP induced measurable killing in ex vivo assays using clinical HCC specimens and, in the prophylactic setting, was associated with enhanced memory-like T-cell responses.

Conclusion

DEXAGNP is a modular exosome vaccine that combines epitope-specific antigen presentation with immune activation and PD-L1 blockade, enabling robust antitumor T-cell responses across complementary liver cancer models. This engineered DEX platform provides a practical blueprint for developing next-generation exosome-based cancer vaccines.

Graphical abstract