最近的研究表明，肠道微生物群及其代谢物可以调节免疫细胞的抗肿瘤免疫力，然而潜在机制仍不清楚。在这里，我们展示了非小细胞肺癌（NSCLC）患者循环CD8+和Vγ9 Vδ2（Vδ2 +）T细胞表面的程序性细胞死亡-1（PD-1）表达与血清丁酸水平呈正相关。反应组NSCLC患者的血清乙酸，丙酸和丁酸水平较非反应组更高。扩展肠道微生物群可使肿瘤携带小鼠的粪便和血清中的丁酸水平降低。机理上，丁酸可以增加人类CD8+ T细胞Pdcd1和Cd28的启动子区域组蛋白3赖氨酸27乙酰化（H3K27ac），从而促进PD-1/CD28的表达并增强抗PD-1疗法的疗效。丁酸补充剂通过调节T细胞受体（TCR）信号通路，在细胞毒性CD8+ T细胞中提高抗肿瘤细胞因子的表达。总的来说，我们的研究结果表明，肠道微生物代谢物丁酸通过调节细胞毒性CD8 T细胞的TCR信号传导，促进了抗PD-1免疫治疗的疗效，并且是一个极具前景的增强抗肿瘤免疫力的治疗生物标志物。

Recent studies have demonstrated that the antitumor immunity of immune cells can be modulated by gut microbiota and their metabolites. However, the underlying mechanisms remain unclear. Here, we showed that the serum butyric acid level is positively correlated with the expression of programmed cell death-1 (PD-1) on circulating CD8+ and Vγ9 Vδ2 (Vδ2+) T cells in patients with non-small cell lung cancer (NSCLC). Responder NSCLC patients exhibited higher levels of serum acetic acid, propionic acid, and butyric acid than non-responders. Depletion of the gut microbiota reduces butyrate levels in both feces and serum in tumor-bearing mice. Mechanistically, butyrate increased histone 3 lysine 27 acetylation (H3K27ac) at the promoter region of Pdcd1 and Cd28 in human CD8+ T cells, thereby promoting the expression of PD-1/CD28 and enhancing the efficacy of anti-PD-1 therapy. Butyrate supplementation promotes the expression of antitumor cytokines in cytotoxic CD8+ T cells by modulating the T-cell receptor (TCR) signaling pathway. Collectively, our findings reveal that the metabolite butyrate of the gut microbiota facilitates the efficacy of anti-PD-1 immunotherapy by modulating TCR signaling of cytotoxic CD8 T cells, and is a highly promising therapeutic biomarker for enhancing antitumor immunity.