αPD-1-conjugated acid-cleavable nanodrugs overcomes cellular immunotherapy barriers in pancreatic tumors.

Abstract

Overcoming barriers in solid tumor immunotherapy remains challenging, with adoptive T cell therapies limited by antigen loss, poor tumor infiltration, and T cell exhaustion. Here, we present a nanoengineered tumor-infiltrating lymphocyte (TIL) therapy using anti-PD-1 antibody (αPD-1)-conjugated ZIF-8 nanoparticles to effectively suppress pancreatic tumor growth. These nanoparticles release hyaluronidase (HAase) and decitabine (DEC) in acidic tumor microenvironments, promoting stroma degradation and C-C motif chemokine ligand 5 (CCL5) secretion, while retaining αPD-1 on TILs to prevent exhaustion. CCL5 recruits additional nanodrug-loaded TILs for further release of HAase and DEC, establishing a self-reinforcing infiltration loop. This approach increases TIL infiltration by 12-fold in immunodeficient mice and, in immunocompetent settings, mobilizes both exogenous TILs and endogenous CD8⁺ T cells, enabling tumor eradication and metastasis suppression with 10-fold lower TIL doses than conventional therapies. Collectively, this nanoengineered TIL therapy offers a potential strategy for addressing immune-resistant tumors, showing distinct benefits in stromal-rich settings.