Six birds with one stone: STING-activating photo-vaccination with glutamine metabolism reprogramming and cascade mitochondrial dysfunction for robust immune landscape remodeling

Abstract

Autologous tumor cells hold great promise as personalized therapeutic vaccines. Nevertheless, the metabolic competition between tumor cells and the functional immune cells limits patient responses to autologous vaccine via fostering immunosuppressive microenvironment and facilitating immune escape. Herein, the STING-activating Photo-vaccination Inducer (BMA) is developed which can shift in immunological state from “cold” to “hot” by tumor metabolic reprogramming and the release of autologous tumor vaccines. BMA can form into peroxidase mimics in situ upon external energy stimulation, enabling continuous production of reactive oxygen species (ROS) through photodynamic effects and photosensitizer recycling. Tumor metabolic reprogramming with continually ROS generation facilitates maturation of dendritic cells (DCs) and reeducation of tumor immune landscape due to spatiotemporally cascading mitochondrial and nucleus dysfunction, leading to in situ nucleic acid vaccine release and stimulator of the interferon genes (STING) pathway activation. As anticipated, results from Cytometry by Time-Of-Flight (CyTOF) results indicate that the tumor landscape has been altered, effectively eradicating primary tumors and inducing beneficial “Abscopal Effects” that counteract checkpoint blockade (ICB) resistance. Our work for the first time leverages a universal and novel strategy of free radical therapy and personalized therapeutic vaccine for tumor immunoscape re-education thereby enhancing αPD-L1 blockade, presenting a rational way to surmount immunotherapy barriers to available clinical treatments.