Microsatellite Instability in the Tumor Microenvironment: The Role of Inflammation and the Microbiome

Background: Microsatellite instability (MSI) is a hallmark of DNA mismatch repair (MMR) deficiency that leads to genomic instability and increased cancer risk. The tumor microenvironment (TME) significantly influences MSI-driven tumorigenesis, and emerging evidence points to a critical role of the microbiome in shaping this complex interplay. Methods: This review comprehensively examines the existing literature on the intricate relationship between MSI, microbiome, and cancer development, with a particular focus on the impact of microbial dysbiosis on the TME. Results: MSI-high tumors exhibited increased immune cell infiltration owing to the generation of neoantigens. However, immune evasion mechanisms such as PD-1/CTLA-4 upregulation limit the efficacy of immune checkpoint inhibitors (ICIs) in a subset of patients. Pathobionts, such as Fusobacterium nucleatum and Bacteroides fragilis, contribute to MSI through the production of genotoxins, further promoting inflammation and oxidative stress within the TME. Conclusions: The microbiome profoundly affects MSI-driven tumorigenesis. Modulation of the gut microbiota through interventions such as fecal microbiota transplantation, probiotics, and dietary changes holds promise for improving ICI response rates. Further research into cancer pharmacomicrobiomics, investigating the interplay between microbial metabolites and anticancer therapies, is crucial for developing personalized treatment strategies.