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D-peptide-nanodrug conjugates synergize VISTA blockade and innate activation for cancer immunotherapy

Beibei Li1, Qingchao Wang2, Xiaoxi Wang3

  • 1School of Life Sciences, Zhengzhou University, Zhengzhou 450001, China.

Journal of Controlled Release : Official Journal of the Controlled Release Society
|July 23, 2026
PubMed

Insights

New D-peptide nanodrugs combine V-domain Ig suppressor of T cell activation (VISTA) blockade with innate immune activation. This approach overcomes tumor microenvironment (TME) suppression, enhancing cancer immunotherapy effectiveness.

Area of Science:

  • Immunology
  • Nanomedicine
  • Oncology

Background:

  • V-domain Ig suppressor of T cell activation (VISTA) signaling and myeloid-derived suppressor cells (MDSCs) impede effective cancer immunotherapy within the tumor microenvironment (TME).
  • Overcoming these suppressive elements is crucial for enhancing therapeutic outcomes in cancer treatment.

Purpose of the Study:

  • To develop novel D-peptide-nanodrug conjugates that synergistically combine VISTA blockade with innate immune activation.
  • To engineer a stimuli-responsive nanoplatform for targeted drug delivery within the TME.

Main Methods:

  • Development of Reorpn7, a stable D-peptide VISTA inhibitor, and co-loading it with a toll-like receptor 7/8 (TLR7/8) agonist (R848) into a matrix metalloproteinase-2 (MMP-2) responsive poly lactic-co-glycolic acid (PLGA) nanoplatform (r7PL-PLGA@R848).
  • Evaluation of the nanoplatform's efficacy in MC38 tumor models, assessing intratumoral immune cell infiltration, antitumor activity, and systemic toxicity.

Main Results:

  • The r7PL-PLGA@R848 nanoplatform demonstrated MMP-2 responsive cleavage in the TME, enabling precise release of Reorpn7 and R848.
  • Significant increase in intratumoral CD8+ T cell infiltration and robust antitumor efficacy were observed in MC38 tumor models.
  • The treatment achieved synergistic VISTA blockade and innate immune activation without significant systemic toxicity.

Conclusions:

  • The developed nanodrug conjugate effectively reshapes the TME from an immunosuppressive to an immunosupportive state.
  • This stimuli-responsive nanoplatform offers a promising strategy to overcome immune checkpoint blockade resistance in challenging malignancies.
  • The approach holds potential for translatable applications in cancer immunotherapy.
Keywords:
Cancer immunotherapyImmune checkpointPeptideTLR7/8 agonistVISTA

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