微卫星稳定 (MSS) 结直肠癌 (CRC) 通常对抗程序性死亡 1 (PD-1) 疗法有抵抗力。在这里，我们发现 CRC 病原体，具核梭杆菌 (Fn)，矛盾地使 MSS CRC 对抗 PD-1 敏感。与来自 Fn 低 MSS CRC 患者的粪便微生物群移植 (FMT) 至携带 MSS CRC 的无菌小鼠相比，Fn 低小鼠的粪便微生物群移植 (FMT) 赋予了对抗 PD-1 的敏感性。单次 Fn 给药还可增强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 功效。从机制上讲，我们证明肿瘤内 Fn 产生丰富的丁酸，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，缓解 CD8 T 细胞耗竭并促进效应器功能。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，肿瘤内高 Fn 预示着对抗 PD-1 治疗的良好反应，表明 Fn 作为 MSS CRC 免疫治疗反应的潜在生物标志物。版权所有 © 2024 作者。由爱思唯尔公司出版。保留所有权利。

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.Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.