Multifunctional Manganese‐Based Nanocomposites for Enhanced Immunotherapy by Regulating Lactate Metabolism and Activating the cGAS‐STING Pathway

ABSTRACT The efficacy of tumor immunotherapy is frequently hindered by immunosuppressive tumor microenvironments (TME). Activating the cyclic guanosine monophosphate‐adenosine monophosphate synthase stimulator of interferon genes (cGAS‐STING) pathway and depleting the tumor metabolic byproduct lactate offer promising strategies to reverse the immunosuppressive TME and enhance immunotherapy efficacy. In this study, multifunctional honeycomb manganese oxide nanocomposites (AL@hM) loaded with banoxantrone (AQ4N) and lactate oxidase are designed to activate the cGAS‐STING pathway and deplete lactate for achieving potent cancer immunotherapy. Upon internalization by tumor cells, lactate oxidase catalyzes the oxidation of lactate, generating hydrogen peroxide and exacerbating hypoxia, thereby reducing lactate levels within both tumor cells and the TME. This lactate depletion promotes cGAS activation and immunosuppressive TME reprogramming. Concurrently, hypoxia‐mediated toxic 1,4‐diazabicyclo[2.2.2]octane‐1,4‐dione (AQ4) production and manganese ions‐driven reactive oxygen species generation facilitate the accumulation of cytosolic double‐stranded DNA (dsDNA). These processes collectively enhance the sensitivity of manganese ions‐dsDNA‐cGAS recognition, leading to robust activation of the cGAS‐STING pathway and strong immune response. This study presents an innovative strategy that combines activation of the cGAS‐STING pathway and lactate metabolism regulation to remodel the tumor immune microenvironment for potentiating immunotherapy outcomes.