Intratumoral P. copri Reprograms MARCO+ Tumor-Associated Macrophages by Depleting Glycerophosphocholine to Drive Colorectal Cancer Progression.

Abstract Colorectal cancer (CRC) is characterized by a complex tumor microenvironment (TME) shaped by intestinal microbiota. In this study, 16S rRNA sequencing of CRC patient tissues identified Prevotella, particularly the dominant species Prevotella copri (P. copri), as a key intratumoral bacterium. The parenchymal invasion of P. copri was confirmed by fluorescence in situ hybridization (FISH), and the abundance of P. copri correlated with advanced tumor stages and postoperative serological markers. Notably, the reduced abundance of P. copri in paired normal tissues implied potential bacterial translocation during tumorigenesis. In multiple murine models, P. copri not only accelerated tumor growth but also reprogrammed tumor-associated macrophages (TAMs) toward a pro-tumoral state. Untargeted metabolomics revealed glycerophosphocholine (GPC) as the only conserved metabolite depleted by P. copri across murine models and bacterial cultures, a finding confirmed by spatial metabolomics in clinical specimens. Strikingly, GPC supplementation reprogrammed MARCO+ TAMs toward an anti-tumoral phenotype, effectively counteracting P. copri-mediated tumor progression. Overall, this study uncovers a paradigm in CRC pathogenesis in which P. copri creates an immunosuppressive niche by depleting GPC to manipulate macrophage polarization. These findings position P. copri as both a non-invasive diagnostic marker and druggable therapeutic target, with GPC restoration representing a promising immunometabolic intervention strategy.