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Enzymatically responsive nanocarriers targeting PD-1 and TGF-β pathways reverse immunotherapeutic resistance and

Ying-Tzu Yen1, Zhifan Zhang1, Anni Chen2

  • 1The Comprehensive Cancer Center of Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, 210008, China.

Journal of Nanobiotechnology
|February 19, 2025
PubMed

Insights

Gelatinase-responsive nanoparticles (GPNPs) deliver dual immunotherapy for lung cancer, enhancing T-cell and macrophage activity. This approach effectively inhibits tumor growth with reduced side effects, offering a promising new treatment strategy.

Area of Science:

  • Oncology
  • Immunology
  • Nanotechnology
  • Biomedical Engineering

Background:

  • Immune checkpoint inhibitors (ICIs) have transformed lung cancer therapy but face resistance and toxicity issues.
  • Dual inhibition of PD-1/PD-L1 and TGF-β pathways is a potential strategy to overcome resistance.
  • Existing combination therapies exhibit limited efficacy and significant systemic side effects.

Purpose of the Study:

  • To develop and evaluate novel gelatinase-responsive nanoparticles (GPNPs) for co-delivery of anti-PD-1 (αPD-1) and galunisertib (Gal), a TGF-β receptor I inhibitor.
  • To assess the efficacy and safety of GPNPs in inhibiting lung cancer progression.
  • To elucidate the underlying mechanisms of GPNP-mediated therapeutic effects on the tumor microenvironment.

Main Methods:

  • Construction of GPNPs encapsulating αPD-1 and Gal for targeted delivery.
  • In vivo efficacy studies in lung cancer models to evaluate tumor progression inhibition.
  • Immune profiling using cytometry assays to analyze tumor-infiltrating lymphocytes (TILs) and macrophages.
  • Transcriptomic analysis and histological assessments (collagen, αSMA) to evaluate extracellular matrix modulation.
  • Fate mapping studies to track fibroblast differentiation.

Main Results:

  • GPNPs demonstrated effective inhibition of lung cancer tumor progression with no observable side effects.
  • Significant recruitment of activated and exhausted TILs and macrophages into the tumor microenvironment was observed.
  • Transcriptomic data revealed modulation of the extracellular matrix, evidenced by reduced collagen deposition and αSMA expression.
  • Fate mapping indicated a reversal of fibroblast transition to myofibroblasts, potentially overcoming an 'immune-exclusive' tumor phenotype.

Conclusions:

  • GPNPs represent a potent platform for dual lung cancer immunotherapy, combining αPD-1 and Gal delivery.
  • The GPNP strategy effectively remodels the tumor microenvironment and enhances anti-tumor immune responses.
  • This approach offers a promising therapeutic strategy with mechanistic insights for improved lung cancer treatment and clinical translation.
Keywords:
Drug resistanceImmune checkpoint inhibitorsPolymeric nanoparticlesTransforming growth factor-βTumor microenvironment

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