Fusobacterium nucleatum-derived succinic acid induces tumor resistance to immunotherapy in colorectal cancer
Fusobacterium nucleatum-derived succinic acid induces tumor resistance to immunotherapy in colorectal cancer
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DOI：
10.1016/j.chom.2023.04.010
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发表时间：
2023-05-10
影响因子：
30.3
通讯作者：
Fang, Jing-Yuan
中科院分区：
文献类型：
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作者：
Jiang, Shan-Shan;Xie, Yi-Le;Fang, Jing-Yuan
抗PD-1单抗免疫检查点阻断治疗是结直肠癌的一种治疗方法。然而，一些患者对PD-1阻断仍然没有反应。肠道微生物区系通过不清楚的机制与免疫治疗耐药有关。我们发现，免疫治疗无效的转移性结直肠癌患者有更多的核梭杆菌和更多的琥珀酸。粪便微生物区系的转移来自低核酸菌应答者，而不是高核酸菌无应答者，赋予小鼠对抗PD-1单抗的敏感性。机制上，核藻来源的琥珀酸抑制cGAS-干扰素-b途径，从而通过限制体内CD8+T细胞向肿瘤微环境(TME)的转运而抑制抗肿瘤反应。用抗生素甲硝唑治疗可降低肠道内核纤毛虫的丰度，从而降低血清琥珀酸水平，并使体内肿瘤对免疫治疗重新敏感。这些发现表明，核杆菌和琥珀酸可诱导肿瘤对免疫治疗产生抵抗力，这为研究结直肠癌的微生物代谢-免疫串扰提供了新的见解。
Immune checkpoint blockade therapy with anti-PD-1 monoclonal antibody (mAb) is a treatment for colorectal cancer (CRC). However, some patients remain unresponsive to PD-1 blockade. The gut microbiota has been linked to immunotherapy resistance through unclear mechanisms. We found that patients with metastatic CRC who fail to respond to immunotherapy had a greater abundance of Fusobacterium nucleatum and increased succinic acid. Fecal microbiota transfer from responders with low F. nucleatum, but not F. nucleatum-high non-responders, conferred sensitivity to anti-PD-1 mAb in mice. Mechanistically, F. nucleatum-derived succinic acid suppressed the cGAS-interferon-b pathway, consequently dampening the antitumor response by limiting CD8+ T cell trafficking to the tumor microenvironment (TME) in vivo. Treat-ment with the antibiotic metronidazole reduced intestinal F. nucleatum abundance, thereby decreasing serum succinic acid levels and resensitizing tumors to immunotherapy in vivo. These findings indicate that F. nucleatum and succinic acid induce tumor resistance to immunotherapy, offering insights into micro -biota-metabolite-immune crosstalk in CRC.