Structure Inversion‐Bridged Sequential Amino Acid Metabolism Disturbance Potentiates Photodynamic‐Evoked Immunotherapy

Abstract Reactive oxygen species (ROS)‐activated immunotherapy is decided by the ROS level and immunosuppressive microenvironment. This report shows the construction of indoleamine 2,3‐dioxygenase (IDO) inhibitor dimers (d‐ss‐DO)‐loaded polymer nanoparticles assembled from Ce6‐tethered disulfide bond‐bridged copolymers. The biomimetic polymeric nanoparticles can serve as glutathione peroxidase to deplete glutathione (GSH) and realize the dense‐to‐loose structure inversion (SI) arising from GSH‐triggered disulfide bonds breakage, which favors d‐ss‐DO release and GSH‐arised d‐ss‐DO cleavage into monomer. This sequential GSH metabolism disturbance can break the redox equilibrium and induce cell dyshomeostasis for facilitating more ROS accumulation and removing cancer stress protection in the photodynamic process. More significantly, the cleaved monomer modulates tryptophan (Trp) metabolism for blockading IDO immune escape target and liberating IDO‐induced immune dampening effect, which along with massively accumulated ROS, mitigates the immunosuppressive microenvironment for potentiating systematic immune responses and increasing tumor vulnerability especially after combining with anti‐PD‐L1. Thus, the SI‐bridged sequential amino acid (i.e., GSH, Trp) metabolism disturbance brings about the largest photodynamic‐evoked immunotherapeutic consequences against breast cancer and melanoma via altering the expressions of apoptosis—amino acids biosynthesis—and glycolysis/gluconeogenesis‐related genes, thus holding high potential in ROS‐activated immunotherapy.