Gastrointestinal Cancers: What Is the Real Board of Microenvironment and the Role of Microbiota–Immunity Axis?

The tumor microenvironment (TME) represents a complex and dynamic entity, able to affect oncogenesis, tumor cells’ preservation, local invasion, and metastatic propagation of gastrointestinal cancers. The TME is able to change according to malignancy type, but common characteristics include immune cells, blood vessels, stromal cells, and extracellular matrix. Moreover, emerging evidence includes also the gut microbiome (GM) in the TME and, in particular, its mutual interplay with the immune response (named microbiome–immunity axis), in gastrointestinal cancers. In this scenario, the reciprocal interaction between cancer cells, immune system, and GM leads to new thinking on the TME borders’ redefinition in the field of gastrointestinal cancers. In this chapter, we retraced the most important studies on the crosstalk between microbiome (and its metabolites) and immune response, and how it affects the TME of gastrointestinal cancers. We discussed the multiple layers of the TME within the holobiont vision and examined how microbial dysbiosis could influence the mutual relationship between the host immunology and GM in several districts of the gastrointestinal tract, affecting oncogenesis, tumor progression, and response to immunotherapy treatment. A deep understanding of all the actors and dynamics of TME in the gastrointestinal tract will allow the design of more effective and tailored therapies, able to target specific TME levels and components, associated with the malignancy development and progression.