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

Abstract

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.