MnO2-Assisted Photosynthetic Bacteria Interfering with the Adenosine-A2AR Metabolic Pathway to Enhance Tumor Photothermal Immunotherapy

Abstract

Hypoxia-related adenosine (Ado) exerts an immunosuppressive effect in tumors by binding to the metabolic checkpoint Ado A2A receptors (A2AR), thereby hindering the activation of antitumor immunity induced by immunogenic cell death (ICD). In this study, a MnO₂-assisted photosynthetic bacteria (PSB) biohybrid (MnO₂@PSB) is developed to enhance tumor photothermal immunotherapy by interfering with the Ado-A2AR metabolic pathway. Specifically, manganese dioxide (MnO₂) nanoflowers are conjugated onto PSB by the carbodiimide reaction to construct the biohybrid MnO₂@PSB. As a photothermal agent, MnO₂@PSB generates heat to “burn” tumor cells under 808 nm laser irradiation, inducing tumor cell ICD. Meanwhile, MnO₂@PSB catalyzes the decomposition of endogenous hydrogen peroxide into oxygen to alleviate tumor hypoxia, thereby reducing Ado production and downregulating the expression of A2AR, further reversing the tumor immunosuppressive microenvironment and amplifying the ICD effects. In various mouse 4T1 tumor models, MnO₂@PSB can enhance antitumor immune responses, prolong mouse survival, and significantly inhibit tumor growth, recurrence, and metastasis under 808 nm laser irradiation. Collectively, this study provides a direction for enhanced antitumor immunotherapy through regulating metabolic pathways.