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Programmable immunoprobiotics orchestrate antitumor immune response with Pin1 inhibition for pancreatic cancer

Sichen Yuan1,2,3, Xicheng Yang1, Alexa M Bremmer1

  • 1Pharmaceutical Sciences Division, School of Pharmacy, University of Wisconsin-Madison, Madison, WI 53705.

Proceedings of the National Academy of Sciences of the United States of America
|August 19, 2025
PubMed

Insights

A novel immunoprobiotic system targets pancreatic cancer by inhibiting Pin1 and blocking PD-L1. This approach remodels the tumor microenvironment, enhancing T cell immunity and improving treatment outcomes in preclinical models.

Area of Science:

  • Oncology
  • Immunotherapy
  • Biotechnology

Background:

  • Pancreatic ductal adenocarcinoma (PDAC) is aggressive, with a desmoplastic and immunosuppressive tumor microenvironment (TME) limiting treatment efficacy.
  • Immune checkpoint blockade (ICB) shows limited success in PDAC due to stromal barriers and low immunogenicity.
  • Pin1 (Peptidyl-prolyl cis/trans isomerase NIMA-interacting 1) is implicated in fibrosis and immune evasion within the TME.

Purpose of the Study:

  • To develop a dual-action delivery system combining Pin1 inhibition and PD-L1 blockade to remodel the PDAC TME and enhance immunotherapy.
  • To investigate the efficacy of this programmable immunoprobiotic system in preclinical PDAC models.

Main Methods:

  • Engineered Escherichia coli Nissle 1917 (EcN) to deliver nanoparticles (Nbs-NP@API-1) containing a Pin1 inhibitor (API-1) to PDAC.
  • The system was designed for sustained release of API-1 to degrade fibrotic stroma and upregulate PD-L1.
  • Engineered EcN also produced anti-PD-L1 nanobodies in situ to synergize with API-1.

Main Results:

  • The EcN@Nbs-NP@API-1 system successfully remodeled the TME in orthotopic PDAC mouse models.
  • Enhanced immune cell infiltration, particularly CD8+ T cells, was observed.
  • Significant antitumor response was achieved with minimized systemic toxicity.
  • Efficacy was also demonstrated in triple-negative breast cancer models.

Conclusions:

  • This programmable immunoprobiotic platform effectively overcomes immunotherapy resistance in PDAC by targeting the TME.
  • The dual-action approach of Pin1 inhibition and PD-L1 blockade shows broad potential for treating ECM-rich solid tumors.
  • This strategy represents a promising advancement in cancer immunotherapy.
Keywords:
Pin1 inhibitiondrug deliveryimmune checkpoint blockadeimmunoprobioticspancreatic ductal adenocarcinoma

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