Escherichia coli promotes colorectal cancer metastasis by maintaining enhancer-promoter loops through releasing neutrophil extracellular traps.

The involvement of intestinal microbiota in the process of neutrophil-mediated colorectal cancer liver metastasis (CRCLM) is not yet fully understood. Here, we show that Escherichia coli (E. coli) is prevalent in CRC tissues with LM using 2bRAD-M-Seq and is linked to the release of neutrophil extracellular traps (NETs). Utilizing multi-omics and molecular techniques, we establish that E. coli recruits RIPK2, which promotes the binding of HNRNPK to the Atf3/Relb promoters in neutrophils, thereby enhancing their transcription. This process results in the upregulation of Ncf4, which triggers p-MLKL-mediated NET formation. NETs, in turn, increase the expression of TRPC1 and NFATC3 in CRC cells, promoting the calcium-dependent assembly of the STAT3/S100A8/9 heterotrimer. This trimer stabilizes STAT3-enhancer-promoter loops (EPLs), thereby reinforcing the Tns1 transcription and facilitating CRCLM. Our findings elucidate the mechanism by which E. coli-induced NETs promote CRCLM through epigenetic modifications, offering an insight into the role of EPLs in immune regulation and tumor progression.