The gut microbiome is a key player in the immunomodulatory and protumorigenic microenvironment during colorectal cancer (CRC), as different gut-derived bacteria can induce tumour growth. However, the crosstalk between the gut microbiome and the host in relation to tumour cell metabolism remains largely unexplored. Here we show that formate, a metabolite produced by the CRC-associated bacterium Fusobacterium nucleatum, promotes CRC development. We describe molecular signatures linking CRC phenotypes with Fusobacterium abundance. Cocultures of F. nucleatum with patient-derived CRC cells display protumorigenic effects, along with a metabolic shift towards increased formate secretion and cancer glutamine metabolism. We further show that microbiome-derived formate drives CRC tumour invasion by triggering AhR signalling, while increasing cancer stemness. Finally, F. nucleatum or formate treatment in mice leads to increased tumour incidence or size, and Th17 cell expansion, which can favour proinflammatory profiles. Moving beyond observational studies, we identify formate as a gut-derived oncometabolite that is relevant for CRC progression.

肠道微生物组是结直肠癌 (CRC) 期间免疫调节和促肿瘤微环境的关键参与者，因为不同的肠道来源的细菌可以诱导肿瘤生长。然而，肠道微生物组和宿主之间与肿瘤细胞代谢相关的串扰在很大程度上仍未被探索。在这里，我们发现甲酸是结直肠癌相关细菌具核梭杆菌产生的代谢产物，可促进结直肠癌的发展。我们描述了将 CRC 表型与梭杆菌丰度联系起来的分子特征。F. nucleatum与患者来源的 CRC 细胞的共培养显示出促肿瘤作用，以及代谢转变为增加甲酸分泌和癌症谷氨酰胺代谢。我们进一步表明，微生物组衍生的甲酸盐通过触发 AhR 信号传导来驱动 CRC 肿瘤侵袭，同时增加癌症干性。最后，对小鼠进行具核梭菌或甲酸盐治疗会导致肿瘤发生率或大小增加，以及 Th17 细胞扩张，从而有利于促炎特征。超越观察性研究，我们确定甲酸是一种与结直肠癌进展相关的肠道来源的肿瘤代谢物。