Potentiated Tumor Photo-immunotherapy Based on Glutamine Starvation and Interferon Stimulatory DNA-Activated cGAS-STING Pathway

Photo-immunotherapy combines phototherapy and immunotherapy, which can eliminate primary tumors and induce host immunity to control distant metastases. However, the effectiveness may be attenuated by the tumor defense mechanisms associated with glutamine metabolism regulation. In this work, a self-assembled stimulator was prepared for glutamine-starvation-potentiated photo-immunotherapy, which is composed of telaglenastat as the glutaminase inhibitor, chlorin e6 (Ce6) as the photosensitizer, and interferon stimulatory DNA (ISD). Ce6 transfers energy from light to molecular oxygen, generating reactive oxygen species (ROS). Telaglenastat assists in the downregulation of endogenous glutathione. Thus, ROS neutralization can be prevented, and the photodynamic therapy effect is enhanced. Additionally, the cGAS-STING signaling pathway activated by ISD remodels the tumor microenvironment by polarizing M2-type tumor-associated macrophages into M1, which finally enhances immunogenic cell death. The prepared nanomedicine combines glutamine starvation and a photo-immunotherapy strategy, offering new insights into cancer treatment.