The tumor microenvironment (TME) influences cancer progression and therapy response. Therefore, understanding what regulates the TME immune compartment is vital. Here we show that microbiota signals program mononuclear phagocytes in the TME toward immunostimulatory monocytes and dendritic cells (DCs). Single-cell RNA sequencing revealed that absence of microbiota skews the TME toward pro-tumorigenic macrophages. Mechanistically, we show that microbiota-derived stimulator of interferon genes (STING) agonists induce type I interferon (IFN-I) production by intratumoral monocytes to regulate macrophage polarization and natural killer (NK) cell-DC crosstalk. Microbiota modulation with a high-fiber diet triggered the intratumoral IFN-I-NK cell-DC axis and improved the efficacy of immune checkpoint blockade (ICB). We validated our findings in individuals with melanoma treated with ICB and showed that the predicted intratumoral IFN-I and immune compositional differences between responder and non-responder individuals can be transferred by fecal microbiota transplantation. Our study uncovers a mechanistic link between the microbiota and the innate TME that can be harnessed to improve cancer therapies.

肿瘤微环境 (TME) 影响癌症进展和治疗反应。因此，了解调节 TME 免疫区室的因素至关重要。在这里，我们显示微生物群信号将 TME 中的单核吞噬细胞编程为免疫刺激性单核细胞和树突状细胞 (DC)。单细胞 RNA 测序显示，缺乏微生物群会使 TME 偏向促肿瘤巨噬细胞。从机制上讲，我们表明微生物群衍生的干扰素基因刺激物 (STING) 激动剂诱导肿瘤内单核细胞产生 I 型干扰素 (IFN-I) 以调节巨噬细胞极化和自然杀伤 (NK) 细胞-DC 串扰。高纤维饮食对微生物群的调节触发了肿瘤内 IFN-I-NK 细胞-DC 轴，并提高了免疫检查点阻断 (ICB) 的功效。我们在接受 ICB 治疗的黑色素瘤患者中验证了我们的发现，并表明预测的肿瘤内 IFN-I 和应答者和非应答者个体之间的免疫成分差异可以通过粪便微生物群移植进行转移。我们的研究揭示了微生物群与可用于改善癌症治疗的先天 TME 之间的机制联系。