The Role of the Gut Microbiome in Cancer Immunotherapy: Current Knowledge and Future Directions

SIMPLE SUMMARY: Cancer immunotherapy is a treatment modality that involves the stimulation of the patient’s immune system to fight off tumors. Although efficient in limiting the disease progression of several solid tumors, including lung cancer and melanoma, some patients may have poor outcomes. This review focuses on the role of the gut microbiota (the microbial community residing in the gastrointestinal tract) in immunity and cancer immunotherapy. Manipulation of the gut microbiota with dietary interventions or fecal microbiota transplantation to enhance response to immunotherapy could pave the way for personalized therapies with improved efficacy. ABSTRACT: Cancer immunotherapy is a treatment modality that aims to stimulate the anti-tumor immunity of the host to elicit favorable clinical outcomes. Immune checkpoint inhibitors (ICIs) gained traction due to the lasting effects and better tolerance in patients carrying solid tumors in comparison to conventional treatment. However, a significant portion of patients may present primary or acquired resistance (non-responders), and thus, they may have limited therapeutic outcomes. Resistance to ICIs can be derived from host-related, tumor-intrinsic, or environmental factors. Recent studies suggest a correlation of gut microbiota with resistance and response to immunotherapy as well as with the incidence of adverse events. Currently, preclinical and clinical studies aim to elucidate the unique microbial signatures related to ICI response and anti-tumor immunity, employing metagenomics and/or multi-omics. Decoding this complex relationship can provide the basis for manipulating the malleable structure of the gut microbiota to enhance therapeutic success. Here, we delve into the factors affecting resistance to ICIs, focusing on the intricate gut microbiome–immunity interplay. Additionally, we review clinical studies and discuss future trends and directions in this promising field.