The efficacy of
cancer immunotherapy largely depends on the tumor microenvironment, especially the
tumor immune microenvironment. Emerging studies have claimed that microbes reside within
tumor cells and immune cells, suggesting that these microbes can impact the state of the
tumor immune microenvironment. For the first time, this review delineates the landscape of intra-tumoral microbes and their products, herein defined as the
tumor microbe microenvironment. The role of the
tumor microbe microenvironment in the
tumor immune microenvironment is multifaceted: either as an immune activator, inhibitor, or bystander. The underlying mechanisms include: (I) the presentation of microbial
antigens by
cancer cells and immune cells, (II) microbial
antigens mimicry shared with
tumor antigens, (III) microbe-induced immunogenic cell death, (IV) microbial adjuvanticity mediated by
pattern recognition receptors, (V) microbe-derived metabolites, and (VI) microbial stimulation of inhibitory checkpoints. The review further suggests the use of potential modulation strategies of the
tumor microbe microenvironment to enhance the efficacy and reduce the adverse effects of checkpoint inhibitors. Lastly, the review highlights some critical questions awaiting to be answered in this field and provides possible solutions. Overall, the
tumor microbe microenvironment modulates the
tumor immune microenvironment, making it a potential target for improving
immunotherapy. It is a novel field facing major challenges and deserves further exploration.