Lymph Node-Targeting Nanotherapy Combined with Photothermal Therapy to Potentiate Chimeric Antigen Receptor-T Cell Treatment of Oral Cancer.

Abstract

Oral squamous cell carcinoma (OSCC) is one of the most common cancers in the head and neck. Immunotherapy has emerged as a promising treatment option for metastatic OSCC because of its potential clinical benefits; however, its effectiveness is limited by the immunosuppressive tumor microenvironment (TME), short-lived responses, and poor infiltration. To overcome these issues, we developed a strategy that combines photothermal therapy (PTT) with chimeric antigen receptor (CAR)-T cell immunotherapy. The prepared conjugated polymer nanoparticles (CPNPs) serve as efficient near-infrared-II (NIR-II) photothermal agents, enabling localized PTT and triggering strong immunogenic cell death (ICD) to activate T cells. Moreover, we engineered a lymph node-targeting nanosystem (ApoA1@PNPs) to improve <i>in vivo</i> production of CAR-T cells. Mucin 1 (MUC1)-specific CAR-T cells were designed to enhance tumor antigen recognition. This combined approach helps CAR-T cells reach primary tumor sites more effectively and induces long-lasting systemic immunity. By addressing the main limitations of traditional CAR-T therapy in OSCC, our integrated PTT/CAR-T strategy offers a potential therapeutic approach with significant clinical potential. This dual method aims to improve patient outcomes by achieving better tumor control.