Intratumoral Brevibacillus parabrevifolius inhibits ferroptosis of hepatocellular carcinoma-infiltrating NK cells via NEDD4L_2bRAD-M

It is known that intestinal flora affects the number and function of NK cells through metabolites, thereby regulating the response of tumors to chemotherapy drugs or immunotherapy. However, little is known about whether intratumoral bacteria are involved in NK cell-mediated antitumor innate immunity. In this study, 2bRAD-M analysis was performed on hepatocellular carcinoma and paired tissues to determine the composition of the intratumoral microbiota. Flow cytometry, co-immunoprecipitation, immunoblotting, immunofluorescence, and DNA pull down assays were used to evaluate the relationship between intratumoral bacteria, ferroptosis, and NK cell activity. Here, we found that the intratumoral bacteria Brevibacillus parabrevis (B. parabrevis) inhibited NK cell ferroptosis by promoting lipolysis into acetyl-CoA. Mechanistically, B. parabrevis catalyzed the acetylation of RORC, enhancing its binding to the NEDD4L promoter. NEDD4L induced ubiquitination of iron transporters SLC39A14, SLC39A8, and STEAP3. Functionally, B. parabrevis induced NK cells to differentiate into adaptability, cytotoxicity, and heat shock, inhibiting the terminal phenotype and changing the tumor microenvironment from cold to hot. In conclusion, B. parabrevis enhanced the antitumor response of NK cells by regulating post-translational modifications. Our study identified a new strategy for utilizing intratumor bacteria for clinical treatment.