From Gut Microbial Metabolites to T-Cell Immunity: Short-Chain Fatty Acids in PD-1 Inhibitor Response

Microbial metabolites are one route through which the gut microbiota may influence host immune responses, and short-chain fatty acids (SCFAs) have been widely studied for their potential roles in immune regulation. SCFAs can affect T cells through receptor signaling, histone deacetylase inhibition, and metabolic regulation, and may influence both CD8⁺ effector T cells and regulatory T cells. Clinical studies have reported that SCFA-related microbial features are associated with responses to (protein 1) PD-1 based treatment, while separate studies using direct metabolite measurements have also linked fecal or circulating SCFA levels with treatment outcomes. However, these findings remain mainly observation. The effects of SCFAs also differ according to metabolite type and concentration, tissue compartment, tumor type, treatment setting, and host microbiome background. Therefore, although SCFAs can connect the metabolic functions of the gut microbiota with T cell-mediated anti-tumor immunity, the exact way they induce the effect of PD-1 inhibitors is not yet known. Although the two are good supplements to the regulation of the gut microbiota, more prospective and intervention studies need to be conducted before they can be used clinically.