Engineering Bacteria in Hydrogel for Photo-Triggered Metabolic-Regulation AND-Gated Tumor Immunotherapy

Tumor cells reprogram the energy metabolism and re-shape the microenvironment to maintain their fast proliferation and metastasis, leading to immunosuppression. Inspired by the design of engineered living materials, in this study, the AND-gated living hydrogel for metabolic-regulation enhanced tumor immunotherapy is constructed. Bacteria are genetically rewired to express lactate oxidase or glucose oxidase as two inputs under the control of thermosensitive promoter and then encapsulated inside the NIR-light controlled hydrogel. Triggered by laser, the engineered living hydrogel weakened the glycolysis and improved the mitochondrial respiration of tumor cells. The regulation of energy metabolism potentiated the antitumor immune responses by stimulating T cells, polarizing tumor associated macrophages to M1 phenotype, inducing the immunogenic cell death and stimulating the cGAS/STING pathway. With "high" inputs of two enzymes, the engineered living hydrogel realized the enhanced tumor immunotherapy as the "high" output. An approach of living hydrogel for metabolic-regulation AND-gated tumor immunotherapy is established.