Abstract

Under certain conditions, components of the oral microbiota have been detected in the gastrointestinal tract, implicating oral microbial communities in intestinal immune regulation. However, the mechanisms by which oral microbiota contribute to metastasis at distant organs remain unclear. Here, we demonstrate that the oral bacterium Streptococcus salivarius promotes metastasis of colorectal cancer (CRC) by inducing neutrophil extracellular trap (NET) formation. Mechanistically, S. salivarius induces formation of an IRGM1‐IQGAP1 complex in neutrophils, in which immune‐related GTPase M1 (IRGM1) interacts with IQ motif‐containing GTPase‐activating protein 1 (IQGAP1), leading to activation of Wnt5a signaling and subsequent engagement of the PI3K/AKT pathway, thereby promoting NET formation. Functional validation experiments show that conditional deletion of IRGM1 or pharmacological inhibition of downstream signaling using XAV‐939 markedly attenuates S. salivarius‐ induced NET formation, indicating the requirement of this pathway in the metastatic process. Furthermore, clinical sample analyses reveal that S. salivarius is significantly enriched in the tongue coating and feces of patients with CRC and is elevated within the tumor microenvironment. Together, these findings identify IRGM1‐IQGAP1‐mediated Wnt5a‐PI3K/AKT signaling as a mechanistic link between oral microbiota and neutrophil‐driven immune responses in cancer metastasis. The oral bacterium Streptococcus salivarius promotes colorectal cancer metastasis by inducing neutrophil extracellular trap (NET) formation. Mechanistically, IRGM1–IQGAP1 interaction activates Wnt5a–PI3K/AKT signaling in neutrophils, driving NET‐mediated tumor progression. These findings reveal a mechanistic link between oral microbiota and immune regulation in cancer metastasis.