A Photoactivatable Self-Assembled Nanoagonist for Synergistic Therapy against Pancreatic Ductal Adenocarcinoma.

Abstract

Immunotherapy has revolutionized the cancer treatment paradigm, yet efficient immunotherapeutic responses against immune-cold/desert cancers remain challenging. Herein, we report that photoactivatable nanoagonists yield a potent antitumor synergy of photoimmunotherapy against pancreatic ductal adenocarcinoma (PDAC). The nanoagonist was fabricated by assembling an amphiphilic boron dipyrromethene-derived polymer conjugated with a Toll-like receptor agonist via a photocleavable linker and stimulator of interferon genes agonist. The nanoagonist enables light-induced generation of reactive oxygen species and on-demand release of the agonists to yield synergistic photoimmunotherapy. The produced tumor antigens promote dendritic cell maturation, which is further amplified by these agonists for eliciting adaptive immunity, accompanied by apparently abscopal and long-term memory effects. The nanoagonist further alleviates the fibrosis of tumor stroma and the immunosuppressive microenvironment, leading to the deep infiltrations of clinically used therapeutics and immune cells to yield preferable combinational treatments against PDAC models. These results provide valuable insights into activatable nanoparticles for cancer therapy against immune-desert cancers.