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<p>Immune checkpoint inhibitors (ICIs) have revolutionized lung cancer treatment, yet resistance remains a challenge. Co-inhibition of PD-1/PD-L1 and TGF-β shows promise but faces limited efficacy and systemic toxicity. We developed gelatinase-responsive nanoparticles (GPNPs) delivering anti-PD-1 antibody (αPD-1) and TGF-β receptor I inhibitor galunisertib (Gal). GPNPs effectively inhibit tumor progression without observed side effects. Immune profiling by cytometry assay reveals robust recruitment of both activated and exhausted tumor-infiltrating lymphocytes (TILs) and macrophages. Transcriptomic analysis indicates extracellular matrix modulation, supported by reduced collagen deposition and αSMA expression. Fate mapping demonstrates attenuation of Pdgfrα<sup>+</sup> fibroblast transition to αSMA myofibroblasts, potentially reversing “immune-exclusive” status. This study validates GPNPs as a promising lung cancer immunotherapy platform, offering mechanistic insights for clinical translation and therapeutic enhancement.</p>

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Enzymatically responsive nanocarriers targeting PD-1 and TGF-β pathways reverse immunotherapeutic resistance and elicit robust therapeutic efficacy

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年2月19日

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  • Ying-Tzu Yen,
  • Zhifan Zhang,
  • Anni Chen,
  • Yuling Qiu,
  • Qin Liu,
  • Qin Wang,
  • Chunhua Li,
  • Chun Wang,
  • Xiaoping Qian,
  • Jie Shao,
  • Fanyan Meng,
  • Lixia Yu,
  • Baorui Liu,
  • Rutian Li

摘要

Immune checkpoint inhibitors (ICIs) have revolutionized lung cancer treatment, yet resistance remains a challenge. Co-inhibition of PD-1/PD-L1 and TGF-β shows promise but faces limited efficacy and systemic toxicity. We developed gelatinase-responsive nanoparticles (GPNPs) delivering anti-PD-1 antibody (αPD-1) and TGF-β receptor I inhibitor galunisertib (Gal). GPNPs effectively inhibit tumor progression without observed side effects. Immune profiling by cytometry assay reveals robust recruitment of both activated and exhausted tumor-infiltrating lymphocytes (TILs) and macrophages. Transcriptomic analysis indicates extracellular matrix modulation, supported by reduced collagen deposition and αSMA expression. Fate mapping demonstrates attenuation of Pdgfrα+ fibroblast transition to αSMA myofibroblasts, potentially reversing “immune-exclusive” status. This study validates GPNPs as a promising lung cancer immunotherapy platform, offering mechanistic insights for clinical translation and therapeutic enhancement.