Countering postoperative immune suppression with a self-assembling dendritic cell nanovaccine

Authors:
  • QYQiang Yang
    Qiang Yang
  • TWTongge Wang
    Tongge Wang
  • HZHongrui Zhang
    Hongrui Zhang
  • SHShuheng Huang
    Shuheng Huang
  • YHYanyun He
    Yanyun He
  • RWRunxiu Wei
    Runxiu Wei
  • NYNa Yin
    Na Yin
  • YGYifei Gao
    Yifei Gao
  • LYLiya Yang
    Liya Yang
  • SJShenyao Jin
    Shenyao Jin
  • LMLinjing Mi
    Linjing Mi
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Abstract
Postoperative immune suppression, driven by transforming growth factor β (TGFβ)-mediated dendritic cell (DC) dysfunction, significantly impairs antigen-specific T cell responses and elevates cancer recurrence risk. A key mechanism is TGFβ-mediated lysosomal incompetence in DCs, resulting from loss of lysosomal prosaposin (pSAP). Herein, we developed an in vivo-generated DC vaccine, BAIT (boosting antigen-delivering immunovaccine for T cell priming), which integrated DC recruitment, antigen delivery, and immune activation within a single platform. Inspired by arginine metabolism-driven lysosomal biogenesis and acidification, BAITs were designed with an arginine-enriched self-assembling peptide backbone, in which tumor lysate antigens and CCL20 co-assembled via coordination interactions. When administered early post-surgery, BAITs recruited DCs, promoted antigen internalization, and activated the mTOR pathway to upregulate pSAP expression. This BAIT-driven DC modulation reversed TGFβ-induced impairments in antigen digestion and MHC-peptide complex formation. To optimize precision immunotherapy, we employed a functional precision medicine approach by customizing tumor lysate preparations induced via ferroptosis, necroptosis, or apoptosis. In a murine postoperative cancer model, Apo-BAITs formulated with apoptotic lysates achieved an 85.5% reduction in tumor burden. These findings demonstrate that BAITs target the lysosomal mTOR-pSAP axis to restore DC function, providing a personalized postoperative cancer vaccine strategy to counter surgery-induced immune suppression.
Funding Information
  • Natural Science Foundation of Guangdong Province (2024B1515020025)
  • National Natural Science Foundation of China (52373166)
  • National Natural Science Foundation of China (82073771)
  • National Natural Science Foundation of China (82104085)
  • National Natural Science Foundation of China (52422318)
  • Natural Science Foundation of Hainan Province (325YXQN589)

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