The dynamics and phenotypes of intratumoral myeloid cells during tumor progression are poorly understood. Here we define myeloid cellular states in gliomas by longitudinal single-cell profiling and demonstrate their strict control by the tumor genotype: in isocitrate dehydrogenase (IDH)-mutant tumors, differentiation of infiltrating myeloid cells is blocked, resulting in an immature phenotype. In late-stage gliomas, monocyte-derived macrophages drive tolerogenic alignment of the microenvironment, thus preventing T cell response. We define the IDH-dependent tumor education of infiltrating macrophages to be causally related to a complex re-orchestration of tryptophan metabolism, resulting in activation of the aryl hydrocarbon receptor. We further show that the altered metabolism of IDH-mutant gliomas maintains this axis in bystander cells and that pharmacological inhibition of tryptophan metabolism can reverse immunosuppression. In conclusion, we provide evidence of a glioma genotype-dependent intratumoral network of resident and recruited myeloid cells and identify tryptophan metabolism as a target for immunotherapy of IDH-mutant tumors.

肿瘤进展过程中肿瘤内骨髓细胞的动力学和表型知之甚少。在这里，我们通过纵向单细胞分析来定义神经胶质瘤中的骨髓细胞状态，并证明它们受到肿瘤基因型的严格控制：在异柠檬酸脱氢酶 (IDH) 突变肿瘤中，浸润性骨髓细胞的分化被阻断，导致不成熟的表型。在晚期胶质瘤中，单核细胞衍生的巨噬细胞驱动微环境的耐受性排列，从而阻止 T 细胞反应。我们将浸润性巨噬细胞的 IDH 依赖性肿瘤教育定义为与色氨酸代谢的复杂重组有因果关系，从而导致芳烃受体的激活。我们进一步表明，IDH 突变神经胶质瘤的代谢改变在旁观者细胞中维持了这一轴，并且色氨酸代谢的药理学抑制可以逆转免疫抑制。总之，我们提供了胶质瘤基因型依赖的驻留和募集骨髓细胞的肿瘤内网络的证据，并将色氨酸代谢确定为 IDH 突变肿瘤免疫治疗的靶标。