Gut microbiota reshapes cancer immunotherapy efficacy: Mechanisms and therapeutic strategies

Gut microbiota is essential for maintaining local and systemic immune homeostasis in the presence of bacterial challenges. It has been demonstrated that microbiota play contrasting roles in cancer development as well as anticancer immunity. Cancer immunotherapy, a novel anticancer therapy that relies on the stimulation of host immunity, has suffered from a low responding rate and incidence of severe immune-related adverse events (irAEs). Previous studies have demonstrated that the diversity and composition of gut microbiota were associated with the heterogeneity of therapeutic effects. Therefore, alteration in microbiota taxa can lead to improved clinical outcomes in immunotherapy. In this review, we determine whether microbiota composition or microbiota-derived metabolites are linked to responses to immunotherapy and irAEs. Moreover, we discuss various approaches to improve immunotherapy efficacy or reduce toxicities by modulating microbiota composition. The role of gut microbiota in cancer immunotherapy. Through manipulation of commensals in cancer patients by diet interventions, fecal microbial transplant, prebiotics, probiotics and bacteria consortia, host antitumor immunity can be enhanced by dominance of "beneficial" bacteria in gut lumen and their metabolites. Increased effector T cells and induction of regulatory T cells (Tregs) can be seen in gut-associated lymphoid tissue, which leads to improved clinical outcomes of cancer immunotherapy with lower incidence of immune-related adverse events (fecal microbiota transplant; perforin; granzyme B; Treg).Highlightsimage Gut microbiota has been acknowledged as key regulators in host-mediated anticancer immune response especially during immunotherapy, and antibiotics-induced dysbiosis often leads to resistance to immunotherapy and poor clinical outcomes.Although the mechanisms underlying gut microbiota-mediated potentiating efficacy while ameliorating side effects of immunotherapy differs across bacteria genus and immunotherapy types, it's generally via enhancing anticancer immunity and remodulating the tumor microenvironment.We reviewed the commensal bacteria profiles associated with responders to immunotherapy in various cancer types, characterized by a high diversity with abundance of specific species, which may help predict patients; sensitivity to immunotherapy before treatment.Since the causal relationship between individual gut microbiota and response to immunotherapy, we propose gut microbiota act as the future therapeutic target and adjuvant in personalized anticancer regimen, and reviewed the current dilemma and potential strategies to manipulate gut microbiota towards "beneficial bacteria."