Self-Assembled R848/Chlorin e6 Nanoparticles for Combinatorial Immunotherapy of Head and Neck Squamous Cell Carcinoma

Effective therapeutic approaches against head and neck squamous cell carcinoma (HNSCC), which is a prevalent malignant tumor, are currently lacking. Although immunotherapy has emerged as a promising strategy for treating HNSCC, its efficacy is severely limited by the immunosuppressive tumor microenvironment. Self-delivery nanoparticles, comprising Toll-like receptor (TLR) agonists and photosensitizers, were successfully developed to address this challenge in combinatorial immunotherapy for HNSCC treatment. After intravenous administration, these nanoparticles efficiently accumulated in tumors, enhancing the bioavailability of the agonist and triggering the TLR signaling pathway to remodel the immunosuppressive tumor microenvironment. Simultaneously, the photosensitizers induced immunogenic cell death and activated the stimulator of the interferon gene (STING) pathway in tumor cells via photodynamic therapy. The development of tumors was significantly inhibited by enhancing the antitumor immunity induced by the nanoparticles. This study provided a new paradigm for HNSCC immunotherapy, involving the synergistic regulation of the immune microenvironment with photodynamic therapy.