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

作者：Xueliang Wang, Y. Q. Fang, Wei Liang, Chi Chun Wong, Huanlong Qin, Yaohui Gao, Meinong Liang, Lei Song, Yongxin Zhang, Miao Fan, Chuanfa Liu, Harry Cheuk-Hay Lau, Lixia Xu, Xiaoxing Li, Song Wu, Junlin Wang, Na Wang, Tao Yang, Mengmiao Mo, Xiang Zhang, Fang Jingyuan, Bing Liao, Joseph J.�Y. Sung, Jun Yu · 发表于：Cancer Cell · 年份：2024 · DOI：10.1016/j.ccell.2024.08.019 · 被引用次数：225 · 研究领域：Cancer Immunotherapy and Biomarkers、Gut microbiota and health、Colorectal Cancer Treatments and Studies

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.