肿瘤血管生成和免疫在癌症进展和结果中呈负相关1。在此，我们报道 ZBTB46 是一种抑制性转录因子，也是经典树突状细胞 (DC)2,3 的广泛接受的标记物，可控制肿瘤血管生成和免疫。 Zbtb46 在 DC 和内皮细胞中被肿瘤衍生因子下调，以促进肿瘤的强劲生长。 Zbtb46 下调导致标志性的促肿瘤微环境 (TME)，包括脉管系统功能障碍和免疫抑制状况。对人类癌症数据的分析显示，ZBTB46 低表达与免疫抑制性 TME 和较差的预后存在类似的关联。相比之下，强制表达 Zbtb46 会导致 TME 发生变化，从而限制肿瘤生长。从机制上讲，Zbtb46 缺陷的内皮细胞具有高度血管生成能力，而 Zbtb46 缺陷的骨髓祖细胞上调 Cebpb 并将 DC 程序转向免疫抑制性骨髓谱系输出，这可能解释了癌症中的骨髓谱系偏斜现象。相反，强制 Zbtb46 表达使肿瘤血管正常化，并通过抑制 Cebpb，使骨髓前体细胞偏向免疫刺激性骨髓谱系输出，从而导致免疫热 TME。值得注意的是，Zbtb46 mRNA 治疗与抗 PD1 免疫疗法协同作用，可改善临床前模型中的肿瘤管理。这些发现确定 ZBTB46 是癌症中血管生成和骨髓谱系偏向的关键因素，并表明维持其表达可能具有治疗益处。© 2024。作者获得 Springer Nature America, Inc. 的独家许可。

Tumor angiogenesis and immunity show an inverse correlation in cancer progression and outcome1. Here, we report that ZBTB46, a repressive transcription factor and a widely accepted marker for classical dendritic cells (DCs)2,3, controls both tumor angiogenesis and immunity. Zbtb46 was downregulated in both DCs and endothelial cells by tumor-derived factors to facilitate robust tumor growth. Zbtb46 downregulation led to a hallmark pro-tumor microenvironment (TME), including dysfunctional vasculature and immunosuppressive conditions. Analysis of human cancer data revealed a similar association of low ZBTB46 expression with an immunosuppressive TME and a worse prognosis. In contrast, enforced Zbtb46 expression led to TME changes to restrict tumor growth. Mechanistically, Zbtb46-deficient endothelial cells were highly angiogenic, and Zbtb46-deficient bone marrow progenitors upregulated Cebpb and diverted the DC program to immunosuppressive myeloid lineage output, potentially explaining the myeloid lineage skewing phenomenon in cancer4. Conversely, enforced Zbtb46 expression normalized tumor vessels and, by suppressing Cebpb, skewed bone marrow precursors toward immunostimulatory myeloid lineage output, leading to an immune-hot TME. Remarkably, Zbtb46 mRNA treatment synergized with anti-PD1 immunotherapy to improve tumor management in preclinical models. These findings identify ZBTB46 as a critical factor for angiogenesis and for myeloid lineage skewing in cancer and suggest that maintaining its expression could have therapeutic benefits.© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.