单核细胞衍生的巨噬细胞 (mo-macs) 驱动肿瘤微环境 (TME) 中的免疫抑制，而骨髓 (BM) 中肿瘤增强的骨髓生成为这些细胞群提供能量。在这里，我们对小鼠和肺癌患者的 BM 骨髓祖细胞、循环单核细胞和肿瘤浸润 mo-macs 的连续体进行了配对转录组和染色质分析，以确定促进促肿瘤 mo-macs 的骨髓祖细胞程序。通过分析染色质可及性和组蛋白标记的变化，我们发现肺肿瘤在 BM 骨髓祖细胞中最容易接触到 Nfe2l2 (NRF2)，作为对氧化应激的细胞保护反应。在肺 TME 中，单核细胞分化为 mo-macs 期间，NRF2 活性持续并增加，以调节氧化应激，进而促进代谢适应、抵抗细胞死亡，并有助于免疫抑制表型。 NRF2 基因缺失和药理学抑制显着降低了 TME 中 mo-mac 的存活率和免疫抑制，从而实现 NK 和 T 细胞治疗性抗肿瘤免疫并与检查点封锁策略协同作用。总而言之，我们的研究确定了骨髓祖细胞失调的可靶向表观遗传节点，该节点维持 TME 中的免疫调节 mo-macs。

Monocyte-derived macrophages (mo-macs) drive immunosuppression in the tumor microenvironment (TME) and tumor-enhanced myelopoiesis in the bone marrow (BM) fuels these populations. Here, we performed paired transcriptome and chromatin analysis over the continuum of BM myeloid progenitors, circulating monocytes, and tumor-infiltrating mo-macs in mice and in patients with lung cancer to identify myeloid progenitor programs that fuel pro-tumorigenic mo-macs. Analyzing chromatin accessibility and histone mark changes, we show that lung tumors prime accessibility for Nfe2l2 (NRF2) in BM myeloid progenitors as a cytoprotective response to oxidative stress. NRF2 activity is sustained and increased during monocyte differentiation into mo-macs in the lung TME to regulate oxidative stress, in turn promoting metabolic adaptation, resistance to cell death, and contributing to immunosuppressive phenotype. NRF2 genetic deletion and pharmacological inhibition significantly reduced mo-macs' survival and immunosuppression in the TME, enabling NK and T cell therapeutic antitumor immunity and synergizing with checkpoint blockade strategies. Altogether, our study identifies a targetable epigenetic node of myeloid progenitor dysregulation that sustains immunoregulatory mo-macs in the TME.