Intratumoral Prevotella copri Reprograms MARCO+ Tumor-Associated Macrophages by Depleting Glycerophosphocholine to...

Colorectal cancer is characterized by a complex tumor microenvironment (TME) shaped by intestinal microbiota. In this study, 16S rRNA sequencing of tissues from patients with colorectal cancer identified Prevotella, particularly the dominant species Prevotella copri, as a key intratumoral bacterium. The parenchymal invasion of P. copri was confirmed by FISH, and the abundance of P. copri correlated with advanced tumor stages and postoperative serologic 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 (TAM) toward a protumoral 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 antitumoral phenotype, effectively counteracting P. copri-mediated tumor progression. Overall, this study uncovers a paradigm in colorectal cancer pathogenesis in which P. copri creates an immunosuppressive niche by depleting GPC to manipulate macrophage polarization. These findings position P. copri as both a noninvasive diagnostic marker and druggable therapeutic target, with GPC restoration representing a promising immunometabolic intervention strategy.

Glycerophosphocholine depletion by intratumoral P. copri induces immunosuppressive polarization of MARCO+ macrophages in colorectal cancer, revealing a microbial-metabolic-immune axis that remodels the tumor microenvironment and represents a potential immunotherapeutic target.