The Impact of Gut Microbiota-Derived Metabolites on the Tumor Immune Microenvironment

SIMPLE SUMMARY: The tumor microenvironment (TME) comprises various non-malignant cells and soluble factors that surround cancer cells and which have mostly a pro-tumorigenic role. Growing evidence indicates that commensal bacteria are involved in the pathogenesis and progression but also in the suppression of various human cancers. Recently, bacterial communities that populate solid tumors have been described. This review provides insights into the complex interaction between gut-microbiota-derived metabolites and the cells of the TME. Novel studies indicate that some microbial molecules can be therapeutically exploited to enhance intratumoral immune responses and to improve the efficacy of cancer immunotherapies. ABSTRACT: Prevention of the effectiveness of anti-tumor immune responses is one of the canonical cancer hallmarks. The competition for crucial nutrients within the tumor microenvironment (TME) between cancer cells and immune cells creates a complex interplay characterized by metabolic deprivation. Extensive efforts have recently been made to understand better the dynamic interactions between cancer cells and surrounding immune cells. Paradoxically, both cancer cells and activated T cells are metabolically dependent on glycolysis, even in the presence of oxygen, a metabolic process known as the Warburg effect. The intestinal microbial community delivers various types of small molecules that can potentially augment the functional capabilities of the host immune system. Currently, several studies are trying to explore the complex functional relationship between the metabolites secreted by the human microbiome and anti-tumor immunity. Recently, it has been shown that a diverse array of commensal bacteria synthetizes bioactive molecules that enhance the efficacy of cancer immunotherapy, including immune checkpoint inhibitor (ICI) treatment and adoptive cell therapy with chimeric antigen receptor (CAR) T cells. In this review, we highlight the importance of commensal bacteria, particularly of the gut microbiota-derived metabolites that are capable of shaping metabolic, transcriptional and epigenetic processes within the TME in a therapeutically meaningful way.