Colorectal microenvironment determines the prognosis of colorectal cancer

Abstract Here we aimed to evaluate the feasibility of distinguishing colorectal microenvironments that support cancer cell growth from those that do not. We hypothesized that patients whose non-tumor-bearing tissue (NBT) obtained from the furthest margins of resected cancer specimens resembled the tumor had a poorer prognosis. Patients with colorectal cancer were divided into groups with tumor-supportive (TSM) or healthy microenvironments using bulk RNA sequencing data from 273 paired NBT and tumor samples. Patients in the TSM group exhibited significantly poorer 5-year recurrence-free survival and overall survival compared with those in the healthy microenvironment group. Pathway and 16S rRNA sequencing analyses revealed that NBT and tumors from the TSM group shared a microbiome composition, along with decreased pathway activity related to microvilli maintenance and flavonoid or vitamin metabolic processes. Single-cell RNA sequencing uncovered upregulated interactions between IL1B high neutrophils and OLFM4 + epithelial cells in NBTs from the TSM group, as well as organized microniches in TSM tumors, featuring interactions between EMP1 high epithelial cells, IL1B high neutrophils and GZMK high CD8 + T cells. Collectively, the colorectal microenvironment can serve as a prognostic biomarker to effectively predict cancer invasiveness and tumor-promoting inflammation. Maintaining a healthy colorectal mucosal microenvironment, potentially through dietary intervention, is crucial.