Microbial metabolites function as core regulatory mediators in the host-microbiome interface; short-chain fatty acids (SCFAs) augment CD8+ T-cell function through histone deacetylase (HDAC) inhibition, while the tryptophan metabolite indole-3-propionic acid (IPA) sustains T-cell precursor exhaustion by epigenetically modulating histone H3 lysine 27 (H3K27) acetylation in the T-cell factor 7 (Tcf7) gene super-enhancer region, consequently elevating anti-PD-1 response rates in multiple tumor models, including melanoma [126,128,129]. The gene discussed is CD8A; the disease is neoplasm.