Two-pronged microenvironmental modulation of metal-oxidase cascade catalysis and metabolic intervention for synergistic tumor immunotherapy

Immunotherapy is an emerging treatment modality for tumors after surgery, radiotherapy, and chemotherapy. Despite the potential for eliminating primary tumor cells and depressing cancer metastasis, immunotherapy has huge challenges including low tumor immunogenicity and undesirable immunosuppressive tumor microenvironment (TME). Herein, the two-pronged microenvironmental modulation nanoplatform is developed to overcome these limitations. Specifically, hollow mesoporous MnO₂ (HM) nanoparticles with pH responsive property are prepared and modified with glucose oxidase (GOX) by amide bond, which are further loaded with a potent glutaminase inhibitor CB839 to obtain HM-GOX/CB839. Under the low pH values in TME, HM was disintegrated, thereby releasing Mn²⁺, GOX and CB839. On the one hand, Mn²⁺ can convert H₂O₂ that increased by GOX catalysis in tumors into highly toxic hydroxyl radicals (•OH) and further induce immunogenic cell death (ICD) through the metal-oxidase cascade catalytic reaction, enhancing immunogenicity. On the other hand, GOX and CB839 can block glycolytic and glutamine metabolism pathways, respectively, which effectively reduce the number of immunosuppressive cells and reshape TME, improving anti-tumor immune efficacy. It is demonstrated that HM-GOX/CB839 can effectively activate the body's immunity and inhibit tumor growth and metastasis, providing a potential strategy for comprehensive tumor therapy. STATEMENT OF SIGNIFICANCE: Integrated microenvironmental modulation of metal-oxidase cascade catalysis and metabolic intervention offers a potential avenue for tumor immunotherapy. Under this premise, we constructed a two-pronged microenvironmental modulation nanoplatform (HM-GOX/CB839). On the one hand, the metal oxidase cascade could catalyze the generation of hydroxyl radicals (•OH) and induce immunogenic cell death (ICD), enhancing immunogenicity; on the other hand, metabolic intervention reprogrammed tumor microenvironment to relieve immunosuppression and thereby enhancing anti-tumor immune response. The resulting data demonstrated that HM-GOX/CB839 effectively inhibited tumor growth and metastasis, providing therapeutic potential for cancer immunotherapy.