A Microbial Lipid-ATP Synthase Axis Fuels NK Cell Antitumor Activity.

The gut microbiota influences systemic immunity and cancer through inter-organ communication, but OMV-mediated mechanisms remain unclear. Here, we uncover a previously unrecognized role of Bacteroides intestinalis in restraining extra-intestinal tumor growth via OMVs enriched in sphingosine (SP), a bioactive lipid that directly binds to ATP5F1A-a subunit of the mitochondrial ATP synthase-to enhance NK cell function. This microbial lipid-ATP synthase interaction augments mitochondrial efficiency, reduces reactive oxygen species (ROS) production, and potently upregulates IFN-γsecretion in NK cells, driving increased cytotoxicity and tumor infiltration. Remarkably, OMVs from B. intestinalis or SP administration greatly inhibit murine tumor growth, while their combination with anti-PD-1 therapy enhances systemic antitumor immunity. This study establishes the specific immune activation ability for gut microbial OMVs and highlights microbiota-derived lipid-based immunotherapies.