Fig. 1

Possible mechanisms linking the gut microbiota to anti-tumor immunity. The composition of the gut microbiome may impact immunotherapy efficacy by either acting as (1) an immunosuppressive or (2) an immunostimulatory factor via various non-mutually exclusive mechanisms. (1) Certain commensal bacteria may suppress anti-tumor immunity by skewing immune subset balances towards suppressive phenotypes such as Tregs and MDSCs. Locally in mucosal sites, induction of immunosuppressive cells could be mediated by cytokines released by host cells (such as gut epithelium or immune cells) in response to microbial sensing. Immunosuppressive effects in distant sites, such as active immunosuppression in the TME, could be mediated by trafficking of locally induced suppressor cells. Additionally, bacterial metabolites with immunosuppressive properties might be released into the circulation and promote immunosuppressive cell functions in the TdLN and TME. Chronic inflammation caused by continuous stimulation by PAMPs/MAMPs or epithelial injury could also ultimately contribute to immunosuppression over time. (2) The immunostimulatory effects of the gut microbiota could be mediated by augmented antigenicity, adjuvanticity, or bystander T cell activation. (a) Antigenicity: Cross-reactive T cells driven by bacterial antigens that additionally recognize tumor-associated antigens is one conceivable mechanism. Luminal bacteria or bacterial antigens can be internalized by DCs in the LP via trans-endothelial dendrites extending through the epithelium into the lumen. Goblet cells and M cells can also serve as portals to deliver bacterial antigens to mucosal APCs. Alternatively, disruption of barrier function may allow for the translocation of luminal bacteria and bacterial antigens. Antigen-loaded DCs can migrate from the LP to the MLN and possibly to distant sites such as the TdLN, where they may prime cross-reactive anti-tumor CD8⁺ or CD4⁺ T cells, enhancing cytotoxic T lymphocyte (CTL) function in the TME. (b) Adjuvanticity: PAMPs/MAMPs may condition DCs to be more potent T cell activators, for instance by upregulating costimulatory molecule expression, enhancing antigen presentation, or boosting type I IFN production. Some microbial metabolites could alter immune cell function epigenetically or otherwise to poise innate and adaptive cells in a heightened activation state. (c) Bystander activation: A heightened inflammatory state in the TME driven by pro-inflammatory cytokines released in response to bacterial stimuli may contribute to tumor cell killing by T cell help provided by bacteria-specific T cells to tumor antigen-specific T cells