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.

中文翻译：

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有核梭杆菌促进微卫星稳定型结直肠癌的抗 PD-1 治疗


微卫星稳定 （MSS） 结直肠癌 （CRC） 通常对抗程序性死亡 1 （PD-1） 治疗耐药。在这里，我们表明 CRC 病原体 Nucleatum 梭杆菌 （Fn） 反常地使 MSS CRC 对抗 PD-1 敏感。与 Fn 低 MSS 患者的 FMT 相比，从 Fn 高 MSS CRC 患者到携带 MSS CRC 的无菌小鼠的粪便微生物群移植 （FMT） 赋予对抗 PD-1 敏感性。单次 Fn 给药还增强了小鼠同种异体移植物和携带 MSS CRC 的 CD34 ⁺ 人源化小鼠的抗 PD-1 疗效。从机制上讲，我们证明瘤内 Fn 产生丰富的丁酸，它抑制 CD8 ⁺ T 细胞中的组蛋白脱乙酰酶 （HDAC） 3/8，诱导 Tbx21 启动子 H3K27 乙酰化和表达。TBX21 转录抑制 PD-1，减轻 CD8⁺ T 细胞耗竭并促进效应功能。支持这一观点的是，敲除 Fn 中产生丁酸的基因会消除其抗 PD-1 增强作用。在 MSS CRC 患者中，高瘤内 Fn 预示着对抗 PD-1 治疗的良好反应，表明 Fn 是 MSS CRC 免疫治疗反应的潜在生物标志物。