马克和詹妮弗·利普舒尔茨精密免疫学研究所Miriam Merad团队取得一项新突破。他们报道了骨髓祖细胞失调刺激肿瘤中的免疫抑制巨噬细胞。相关论文于2025年9月10日发表于国际顶尖学术期刊《自然》杂志上。

在这里，课题组对小鼠和肺癌患者的髓系祖细胞、循环单核细胞和肿瘤浸润性mo-macs进行了配对转录组和染色质可及性分析，以确定促进致瘤性mo-macs的髓系祖细胞程序。课题组发现，肺肿瘤在骨髓祖细胞中主要可获得Nfe2l2 (NRF2)，作为氧化应激的细胞保护反应，增强骨髓生成，同时抑制干扰素反应并促进免疫抑制。在TME中，NRF2活性在单核细胞分化为mo-macs的过程中被放大，以调节应激并驱动免疫抑制表型。NRF2基因缺失和药物抑制显著降低TME中mo-macs的存活和免疫抑制，恢复自然杀伤和T细胞抗肿瘤免疫，增强检查点阻断效果。他们的发现确定了骨髓祖细胞失调的一个可靶向的表观遗传节点，该节点在肺TME中维持免疫调节的mo-macs，并强调了早期干预重编程巨噬细胞命运以改善免疫治疗结果的潜力。

据了解，单核细胞来源的巨噬细胞（mo-macs）通常在肿瘤微环境（TME）中驱动免疫抑制，而肿瘤细胞增强的骨髓生成为这些细胞提供了燃料。

附：英文原文

Title: Myeloid progenitor dysregulation fuels immunosuppressive macrophages in tumours

Author: Hegde, Samarth, Giotti, Bruno, Soong, Brian Y., Halasz, Laszlo, Le Berichel, Jessica, Schaefer, Maximilian M., Kloeckner, Benoit, Mattiuz, Raphal, Park, Matthew D., Magen, Assaf, Marks, Adam, Belabed, Meriem, Hamon, Pauline, Chin, Theodore, Troncoso, Leanna, Lee, Juliana J., Fan, Kaili, Ahimovic, Dughan, Bale, Michael J., Nie, Kai, Chung, Grace, Dsouza, Darwin, Angeliadis, Krista, Kim-Schulze, Seunghee, Flores, Raja M., Kaufman, Andrew J., Ginhoux, Florent, Buenrostro, Jason D., Josefowicz, Steven Z., Tsankov, Alexander M., Marron, Thomas U., Ma, Sai, Brown, Brian D., Merad, Miriam

Issue&Volume: 2025-09-10

Abstract: Monocyte-derived macrophages (mo-macs) often drive immunosuppression in the tumour microenvironment (TME)1 and tumour-enhanced myelopoiesis in the bone marrow fuels these populations2. Here we performed paired transcriptome and chromatin accessibility analysis over the continuum of myeloid progenitors, circulating monocytes and tumour-infiltrating mo-macs in mice and in patients with lung cancer to identify myeloid progenitor programs that fuel pro-tumorigenic mo-macs. We show that lung tumours prime accessibility for Nfe2l2 (NRF2) in bone marrow myeloid progenitors as a cytoprotective response to oxidative stress, enhancing myelopoiesis while dampening interferon response and promoting immunosuppression. NRF2 activity is amplified during monocyte differentiation into mo-macs in the TME to regulate stress and drive immunosuppressive phenotype. NRF2 genetic deletion and pharmacological inhibition significantly reduced the survival and immunosuppression of mo-macs in the TME, restoring natural killer and T cell anti-tumour immunity and enhancing checkpoint blockade efficacy. Our findings identify a targetable epigenetic node of myeloid progenitor dysregulation that sustains immunoregulatory mo-macs in the lung TME and highlight the potential of early interventions to reprogram macrophage fate for improved immunotherapy outcomes.

DOI: 10.1038/s41586-025-09493-y

Source: https://www.nature.com/articles/s41586-025-09493-y