The role of gut microbiota in obesity-related cancers

Obesity is an established risk factor for at least thirteen cancer types, yet the mechanisms by which the gut microbiota participates in obesity-related tumorigenesis remain incompletely understood. In this review, we summarize the role of the gut microbiota in the four core oncogenic pathways of obesity including metabolic reprogramming, the obesity-related secretome, hormonal dysregulation, and immune modulation. Mechanistically, microbial activity shapes these processes primarily through the production of metabolites, disruption of the intestinal barrier, and stimulation of innate immunity via microbe-associated molecular patterns, ultimately contributing to chronic low-grade inflammation and impaired antitumor immune surveillance. Nevertheless, many outstanding questions remain. Microbial signals are not uniformly tumor-promoting, in obesity- related liver cancer models, short-chain fatty acid-producing taxa can suppress pro-tumor inflammation. In terms of cancer type, the evidence for mechanistic involvement is strongest for colorectal and liver cancers, owing to the gut-liver axis and direct epithelial exposure, whereas causal inferences for other cancer types remain limited. Moreover, the role of intratumoral microbiota remains uncertain due to low microbial biomass and potential sequencing contamination. Key translational challenges include confounding factors such as diet and co-treatments, inconsistencies in obesity phenotyping across studies, and platform-dependent variability in microbial biomarkers. Nonetheless, microbial interventions aimed at targeting obesity-related cancer development and progression represent a promising avenue for future therapeutic strategies.