肿瘤相关巨噬细胞主要极化为M2表型，通过分泌各种细胞因子重塑肿瘤微环境并促进肿瘤进展。从前列腺癌（PCa）、正常前列腺和PCa患者淋巴结转移样本的组织微阵列中用Yin Yang 1 (YY1)和CD163染色。构建过表达YY1的转基因小鼠观察PCa肿瘤发生。此外，进行CRISPR-Cas9敲除、RNA测序、染色质免疫共沉淀（ChIP）测序和液-液相分离（LLPS）实验等，研究YY1在M2巨噬细胞和PCa肿瘤微环境中的作用和机制。YY1在PCa中的M2巨噬细胞中高表达，与较差的临床结果有关。过表达YY1的转基因小鼠中，浸润肿瘤的M2巨噬细胞比例增加。相反，抗肿瘤的T淋巴细胞的增殖和活性被抑制。使用基于M2巨噬细胞靶向肽修饰的脂质体载体靶向YY1，抑制PCa细胞肺转移，并与PD-1阻断共同产生协同的抗肿瘤效应。IL-4/STAT6途径调节YY1，YY1通过上调IL-6增加巨噬细胞诱导的PCa进展。此外，通过对M2巨噬细胞和THP-1进行H3K27ac-ChIP-seq，发现M2巨噬细胞极化期间获得了数千个增强子，这些M2特异性增强子富集于YY1 ChIP-seq信号中。此外，在M2巨噬细胞中，M2特异性IL-6增强子通过长程染色质互作与IL-6启动子上调IL-6表达。在M2巨噬细胞极化期间，YY1形成LLPS，其中p300、p65和CEBPB充当转录共因子。YY1复合物的相分离在M2巨噬细胞中通过促进IL-6增强子-启动子相互作用上调IL-6，从而增加PCa进展。©作者（或其雇主）2023年。在CC BY-NC许可下允许重新使用。不得商业再利用。由BMJ出版。

Tumor-associated macrophages are mainly polarized into the M2 phenotype, remodeling the tumor microenvironment and promoting tumor progression by secreting various cytokines.Tissue microarray consisting of prostate cancer (PCa), normal prostate, and lymph node metastatic samples from patients with PCa were stained with Yin Yang 1 (YY1) and CD163. Transgenic mice overexpressing YY1 were constructed to observe PCa tumorigenesis. Furthermore, in vivo and in vitro experiments, including CRISPR-Cas9 knock-out, RNA sequencing, chromatin immunoprecipitation (ChIP) sequencing, and liquid-liquid phase separation (LLPS) assays, were performed to investigate the role and mechanism of YY1 in M2 macrophages and PCa tumor microenvironment.YY1 was highly expressed in M2 macrophages in PCa and was associated with poorer clinical outcomes. The proportion of tumor-infiltrated M2 macrophages increased in transgenic mice overexpressing YY1. In contrast, the proliferation and activity of anti-tumoral T lymphocytes were suppressed. Treatment targeting YY1 on M2 macrophages using an M2-targeting peptide-modified liposome carrier suppressed PCa cell lung metastasis and generated synergistic anti-tumoral effects with PD-1 blockade. IL-4/STAT6 pathway regulated YY1, and YY1 increased the macrophage-induced PCa progression by upregulating IL-6. Furthermore, by conducting H3K27ac-ChIP-seq in M2 macrophages and THP-1, we found that thousands of enhancers were gained during M2 macrophage polarization, and these M2-specific enhancers were enriched in YY1 ChIP-seq signals. In addition, an M2-specific IL-6 enhancer upregulated IL-6 expression through long-range chromatin interaction with IL-6 promoter in M2 macrophages. During M2 macrophage polarization, YY1 formed an LLPS, in which p300, p65, and CEBPB acted as transcriptional cofactors.Phase separation of the YY1 complex in M2 macrophages upregulated IL-6 by promoting IL-6 enhancer-promoter interactions, thereby increasing PCa progression.© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.