Oat-β-glucan potentiates anti-PD-1 efficacy through Faecalibacterium prausnitzii-derived butyrate and indole-3-propionic acid.

The gut microbiota governs immune checkpoint blockade responses, yet actionable strategies remain scarce. Here, we report that oat-β-glucan enhances anti-PD-1 (programmed cell death protein 1) efficacy in murine models by selectively expanding Faecalibacterium prausnitzii (F. prausnitzii). Combining anti-PD-1 with either oat-β-glucan or F. prausnitzii boosts intratumoral dendritic cell and CD8+ T cell infiltration and cytotoxic activation compared with anti-PD-1 monotherapy. Metabolomics identifies F. prausnitzii-derived butyrate and indole-3-propionic acid (IPA) as key mediators. Mechanistically, butyrate activates dendritic cells via the histone deacetylase (HDAC)8/H3K27ac/nuclear factor κB (NF-κB) p65 pathway, while both butyrate and IPA potentiate CD8+ T cell effector responses. In our colorectal cancer cohort undergoing anti-PD-1 treatment, higher baseline F. prausnitzii abundance and elevated plasma butyrate and IPA correlate with improved responses, a signature corroborated in independent external cohorts. A human intervention study confirms oat-β-glucan's safety, its ability to increase butyrate and IPA, and its capacity to modulate F. prausnitzii. Collectively, our work uncovers a microbiota-metabolite-immune axis whereby oat-β-glucan primes tumors for immunotherapy sensitization.