肿瘤相关巨噬细胞（TAMs）通常被肿瘤微环境（TME）教育成具有促肿瘤功能的巨噬细胞。巨噬细胞重编程被提出作为一种潜在的肿瘤免疫疗法策略。我们最近证明了锌指蛋白和基因盒2（Zhx2）在巨噬细胞的代谢编程中起关键作用。然而，Zhx2是否负责巨噬细胞极化和TAMs重编程尚不完全清楚。在这里，我们展示了Zhx2在炎症刺激和TME下控制巨噬细胞极化的作用。Zhx2在鼠肝肿瘤模型中特异性地删除巨噬细胞，抑制了LPS诱导的促炎性极化，但促进了IL-4和TME诱导的抗炎性和促肿瘤表型转变。TME中的因素，尤其是乳酸，显著降低了TAMs中Zhx2的表达，导致TAMs转向促肿瘤表型并进一步促进癌症进展。值得注意的是，TAM中ZHX2表达降低与肝细胞癌患者的差生存率相关。机制研究揭示了Zhx2与NF-κB p65结合，并结合到Irf1启动子，从而在巨噬细胞中促进了Irf1的转录活性。Zhx2通过调节Irf1的转录来维持巨噬细胞极化，可能成为巨噬细胞为基础的癌症免疫疗法的潜在靶点。© 2023作者，采用ADMC Associazione Differenziamento e Morte Cellulare的独家许可。

Macrophages are usually educated to tumor-associated macrophages (TAMs) in cancer with pro-tumor functions by tumor microenvironment (TME) and TAM reprogramming has been proposed as a potential tumor immunotherapy strategy. We recently demonstrated the critical role of Zinc-fingers and homeoboxes 2 (Zhx2) in macrophages' metabolic programming. However, whether Zhx2 is responsible for macrophage polarization and TAMs reprogramming is largely unknown. Here, we show that Zhx2 controls macrophage polarization under the inflammatory stimulus and TME. Myeloid-specific deletion of Zhx2 suppresses LPS-induced proinflammatory polarization but promotes IL-4 and TME-induced anti-inflammatory and pro-tumoral phenotypes in murine liver tumor models. Factors in TME, especially lactate, markedly decrease the expression of Zhx2 in TAMs, leading to the switch of TAMs to pro-tumor phenotype and consequent cancer progression. Notably, reduced ZHX2 expression in TAM correlates with poor survival of HCC patients. Mechanistic studies reveal that Zhx2 associates with NF-κB p65 and binds to the Irf1 promoter, leading to transcriptional activation of Irf1 in macrophages. Zhx2 functions in maintaining macrophage polarization by regulating Irf1 transcription, which may be a potential target for macrophage-based cancer immunotherapy.© 2023. The Author(s), under exclusive licence to ADMC Associazione Differenziamento e Morte Cellulare.