Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University and Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China.
Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China.
Oncogene. 2024 Jul;43(31):2389-2404. doi: 10.1038/s41388-024-03080-7. Epub 2024 Jun 18.
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.
肿瘤驻留菌群在调节肿瘤免疫中的作用尚不清楚。在这里，我们发现大量的肿瘤内细菌，如大肠杆菌，存在并导致结直肠癌肝转移（CRLM）。大肠杆菌增强了乳酸的产生，通过雷帕霉素诱导基因 1（RIG-I）的乳酰化作用抑制核因子-κB-基因结合（NF-κB）信号通路，从而介导 M2 巨噬细胞极化。RIG-I 的乳酰化作用抑制了 NF-κB 在巨噬细胞中向 Nlrp3 启动子的募集，从而降低了其转录。Nlrp3 的缺失影响了调节性 T 细胞（Tregs）的免疫抑制活性和 CD8 T 细胞的抗肿瘤活性。小分子化合物筛选发现了一种 RIG-I 乳酰化抑制剂，它抑制了 M2 极化，并使 CRLM 对 5-氟尿嘧啶（5-FU）敏感。我们的研究结果表明，肿瘤驻留菌群可能是预防和治疗 CRLM 的一个潜在靶点。
