Tumor-resident microbiota contributes to colorectal cancer liver metastasis by lactylation and immune modulation
Jian Gu, Xiaozhang Xu, Xiangyü Li, Lei Yue, Xiaowen Zhu, Qiuyang Chen, Ji Gao, Takashi Maruyama, Wenhu Zhao, Bo Zhao, Yue Zhang, Minjie Lin, Jinren Zhou, Yuan Liang, Shipeng Dai, Yufeng Pan, Qing Shao, Li Yu, Yiming Wang, Zibo Xu, Qufei Qian, Tianning Huang, Xiaofeng Qian, Ling Lü
Abstract
Abstract The role of tumor-resident microbiota in modulating tumor immunity remains unclear. Here, we discovered an abundance of intra-tumoral bacteria, such us E.coli , residing and resulting in Colorectal cancer liver metastasis (CRLM). E.coli enhanced lactate production, which mediated M2 macrophage polarization by suppressing nuclear factor-κB -gene binding (NF-κB) signaling through retinoic acid-inducible gene 1 (RIG-I) lactylation. Lactylation of RIG-I suppressed recruitment of NF-κB to the Nlrp3 promoter in macrophages, thereby reducing its transcription. This loss of Nlrp3 affected the immunosuppressive activities of regulatory T cells (Tregs) and the antitumor activities of and CD8 + T cells. Small-molecule compound screening identified a RIG-I lactylation inhibitor that suppressed M2 polarization and sensitized CRLM to 5-fluorouracil (5-FU). Our findings suggest that tumor-resident microbiota may be a potential target for preventing and treating CRLM.