Porphyromonas gingivalis outer membrane vesicles promote oral tumorigenesis through suppressing innate immune surveillance

Several studies have linked microbes to the development of neoplasms, with species of the genus Porphyromonas being closely associated with the progression of oral squamous cell carcinoma (OSCC). However, the immunomodulatory role of Porphyromonas gingivalis (P. gingivalis) outer membrane vesicles (OMVs) in OSCC progression remains unclear. Here, we found that Porphyromonas was significantly enriched in head and neck squamous cell carcinoma, including OSCC tissues. The increased abundance of P. gingivalis in OSCC was confirmed in both saliva and tumor tissues, and correlated with advanced clinical stages. The uptake of P. gingivalis OMVs by OSCC cells was assessed using both in vitro and in vivo models. The OMVs inactivated the cyclic GMP–AMP synthase (cGAS)–stimulator of interferon genes (STING) innate immune signaling, thereby disrupting cytokine production. Herring testis DNA treatment partially restored pIRF3 translocation and induce IFN-β production in vivo. Mechanistically, P. gingivalis OMVs remarkably disrupted both the IRF3–STING and IRF3–TBK1 interaction, consequently blocking the downstream signaling. In both immunodeficient (BALB/c-nu) and immunocompetent (C57BL/6) mouse models, P. gingivalis OMVs suppressed cGAS-STING innate immune signaling, impairing IFN-β production and promoting immune evasion by limiting the recruitment of natural killing cell and dendritic cell to the tumor microenvironment. These findings suggest that P. gingivalis OMVs suppress cGAS–STING–IFN-β innate immune signaling, thereby impairing antitumor immunity.