Fusobacterium nucleatum facilitates anti-PD-1 therapy in microsatellite stable colorectal cancer

Microsatellite stable (MSS) colorectal cancers (CRCs) are often resistant to anti-programmed death-1 (PD-1) therapy. Here, we show that a CRC pathogen, Fusobacterium nucleatum (Fn), paradoxically sensitizes MSS CRC to anti-PD-1. Fecal microbiota transplantation (FMT) from patients with Fn-high MSS CRC to germ-free mice bearing MSS CRC confers sensitivity to anti-PD-1 compared to FMT from Fn-low counterparts. Single Fn administration also potentiates anti-PD-1 efficacy in murine allografts and CD34+-humanized mice bearing MSS CRC. Mechanistically, we demonstrate that intratumoral Fn generates abundant butyric acid, which inhibits histone deacetylase (HDAC) 3/8 in CD8+ T cells, inducing Tbx21 promoter H3K27 acetylation and expression. TBX21 transcriptionally represses PD-1, alleviating CD8+ T cell exhaustion and promoting effector function. Supporting this notion, knockout of a butyric acid-producing gene in Fn abolishes its anti-PD-1 boosting effect. In patients with MSS CRC, high intratumoral Fn predicts favorable response to anti-PD-1 therapy, indicating Fn as a potential biomarker of immunotherapy response in MSS CRC. [Display omitted] •Fn boosts anti-PD-1 efficacy in microsatellite stable colorectal cancer (MSS CRC)•Fn represses PD-1 expression on CD8+ TILs and reactivates their effector functions•Fn-derived butyric acid down-regulates PD-1 on CD8+ TILs via a HDAC3/8-TBX21 axis•High intratumoral Fn abundance correlates with favorable response in MSS CRC Wang et al. report that colorectal cancer (CRC)-promoting gut pathogen Fusobacterium nucleatum paradoxically sensitizes microsatellite stable colorectal cancer (MSS CRC) to anti-PD-1 in experimental models and predicts favorable response to anti-PD-1 in patients with MSS CRC. Mechanistically, F. nucleatum-derived butyric acid relieves CD8+ TIL exhaustion by repressing PD-1 via a HDAC3/8-TBX21 axis.