Butyrate enhances tumor immune evasion by increasing PD-L1 abundance

As a short-chain fatty acid and histone deacetylase (HDAC) inhibitor, butyrate possesses extensive immunomodulatory properties. Here, we uncover a novel mechanism wherein butyrate markedly upregulates the expression of the immune checkpoint PD-L1 across diverse tumor cell types. Mechanistically, epigenetic analyses revealed that butyrate drives PD-L1 transcriptional activation through dual synergistic pathways: increasing histone H3 acetylation (H3Ac) at the PD-L1 promoter via HDAC inhibition, and enhancing histone H3K4me3 modification by upregulating transglutaminase 2 (TGM2). Combining butyrate or high-fiber diets with anti-PD-L1 antibodies profoundly suppressed tumor growth and bolstered anti-tumor immunity in both subcutaneous and AOM-DSS-induced colorectal cancer (CRC) murine models. Ultimately, our results highlight butyrate and dietary fiber supplementation as promising sensitizing strategies to augment the efficacy of PD-L1 blockade in patients with low baseline PD-L1 expression.