Gut microbiota-derived formate exacerbates pulmonary metastasis in cancer

Rationale: The gut microbiota and its metabolites significantly influence cancer development and metastasis. Among these, formate, the simplest short-chain fatty acid (SCFA), remains underexplored in the context of metastasis. This study investigates the role of microbiota-derived formate in exacerbating pulmonary metastasis in melanoma and pancreatic ductal adenocarcinoma (PDAC), aiming to elucidate its mechanistic contributions to cancer progression. Methods: Using antibiotics-induced dysbiosis in mice, we quantified plasma formate levels via nuclear magnetic resonance (NMR) metabolomics and identified gut bacterial contributors through 16S rRNA sequencing. Formate's effects on melanoma and PDAC lung metastases were evaluated through in vivo supplementation experiments. Cellular assays, metabolomics, and gene expression analyses further elucidated its mechanistic impact. Results: Dysbiosis significantly increased circulating formate levels, with Enterobacterales identified as key contributors. Formate supplementation enhanced melanoma and PDAC lung metastases by promoting cancer cell proliferation, migration, and nucleotide synthesis. Mechanistic studies revealed that formate upregulated one-carbon metabolism, critical for tumor aggressiveness, and increased the production of metabolites like glutathione, facilitating oxidative stress resistance. Conclusion: Microbiota-derived formate plays a critical role in enhancing pulmonary metastasis by modulating cancer cell metabolism. These findings highlight the therapeutic potential of targeting formate production or its associated metabolic pathways to mitigate cancer spread. Additionally, microbiome modulation emerges as a promising complementary approach to improving cancer treatment outcomes.