Ampicillin-resistant Klebsiella pneumoniae enhances neutrophil infiltration to induce liver metastasis of colorectal cancer

The increasing focus on intratumoral bacteria research has led to heightened interest in the relationship between intratumoral bacteria and liver metastasis in colorectal cancer. Previous studies have shown that ampicillin-resistant Klebsiella pneumoniae (Am-R-Kp) becomes enriched in the niche following liver metastasis, leading to neutrophil infiltration and enhanced metastatic properties of colorectal cancer cells. However, the precise mechanism underlying this phenomenon remains unclear. Our findings from single-cell RNA sequencing indicated that downregulation of RIPK2 in neutrophils played a crucial role in Am-R-Kp infection. Furthermore, we observed that Kp triggered RIPK2 phosphorylation in neutrophils, leading to increased expression of the transcription factor ATF3/RelB. This, in turn, facilitated the interaction between calc-binding protein S100A8/9 and STAT3 in colorectal cells. Based on these results, we proposed that RIPK2 may mediate ATF3/RelB binding to target gene promoters in neutrophils, thereby promoting neutrophil infiltration and enhancing oncogene expression by modulating the S100A8/9-STAT3-associated enhancer-promoter loop in colorectal cells. Our study will utilize CUT&Tag, HiChIP, flow cytometry, and other technologies to elucidate the interplay between bacteria, neutrophils, and tumor cells, leading to the establishment of a novel theoretical framework supporting the assertion that "intratumoral bacteria facilitate liver metastasis in colorectal cancer." Furthermore, our research identified a potential therapeutic target for the treatment of liver metastasis in colorectal cancer.