Biomineralized Engineered Bacterial Outer Membrane Vesicles as cGAS-STING Nanoagonists Synergize with Lactate Metabolism Modulation to Potentiate Immunotherapy.

Abstract

The immunosuppressive tumor microenvironment (TME) significantly limits the efficacy of cancer immunotherapy. Activation of the cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS) stimulator of interferon genes (STING) pathway and depletion of the tumor metabolic byproduct lactate (LA) represent promising strategies to reverse the immunosuppressive TME and enhance antitumor therapeutic outcomes. Herein, biomineralized engineered bacterial outer membrane vesicles (OMVs@MnCaP-FA) are developed to synergistically activate the cGAS-STING pathway and modulate LA metabolism for antitumor immunotherapy. Upon internalization by 4T1 tumor cells, OMVs@MnCaP-FA undergo acid-responsive degradation, releasing Ca2+, Mn2+, and lactate oxidase (LOX)-expressing OMVs (OMVs-EcL). These components collectively promote mitochondrial DNA (mtDNA) generation, enhance cGAS-mediated mtDNA recognition and cyclic GMP-AMP (cGAMP) production, and potentiate the binding of cGAMP to STING, leading to robust activation of the cGAS-STING signaling pathway. More importantly, OMVs-EcL-mediated LA depletion reprograms the immunosuppressive TME into an immunoresponsive state, revitalizing antitumor immunity. In vivo studies demonstrate that the combined activation of the cGAS-STING pathway and regulation of LA metabolism effectively inhibit primary tumor growth and metastatic progression, highlighting the potential of this synergistic strategy for advancing antitumor immunotherapy.