A Microbial Lipid‐ATP Synthase Axis Fuels NK Cell Antitumor Activity

ABSTRACT 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.