Fusobacterium nucleatum OMVs Promote Macrophage Polarization via TLR2/4-JAK-STAT to Drive Lung Cancer Progression

In this work, we provide novel evidence that F.n-OMVs promote tumor growth and metastasis by modulating the polarization of alveolar macrophages. Through in vivo and in vitro experiments, we demonstrate that F.n-OMVs activate Toll-like receptors (TLR) 2 and 4, leading to the activation of the JAK-STAT pathway.

This, in turn, results in macrophage polarization towards an M2 phenotype, which is known to support tumor progression. Importantly, we show that inhibition of TLR2 and TLR4 signaling alters macrophage polarization, with TLR2 inhibition promoting M1 polarization and suppressing tumor growth, while TLR4 inhibition paradoxically enhances M2 polarization and tumor progression. Our findings reveal a novel and significant mechanism by which the microbiome, specifically F.n., can regulate macrophage behavior within the tumor microenvironment, providing potential therapeutic targets for lung cancer treatment.