魏茨曼科学研究所Ido Amit课题组取得一项新突破。他们的研究显示，ZEB2是控制肿瘤相关巨噬细胞程序的主开关。这一研究成果发表在2025年4月10日出版的国际学术期刊《癌细胞》上。

该研究团队通过将人类肿瘤单细胞RNA测序（scRNA-seq）数据与专用CRISPR筛选相结合，生成了TAM调节网络。利用深度生成模型，该课题组研究人员构建了一个基因扰动网络，将个体候选人与原型TAM函数连接起来。该课题组确定Zeb2是TAM程序的主要调节因子，协调i型干扰素反应和抗原呈递的抑制以及免疫抑制程序的激活。基因消融ZEB2在染色质、RNA和蛋白质水平上重编程TAM的功能和身份。在富含巨噬细胞的人类肿瘤中，ZEB2表达与不良预后相关。选择性Zeb2在体内靶向重编程TAM并调动全身T细胞反应，实现肿瘤清除。总的来说，他们的研究生成了TAM基因回路的详细路线图，并确定ZEB2是具有治疗潜力的主开关。

据介绍，肿瘤相关巨噬细胞（TAMs）是肿瘤免疫逃避的关键介质。然而，人们对它们的调控回路和检查点有部分了解。

附：英文原文

Title: ZEB2 is a master switch controlling the tumor-associated macrophage program

Author: Fadi Sheban, Truong San Phan, Ken Xie, Florian Ingelfinger, Chamutal Gur, Yuval Shapir Itai, Ronnie Blecher-Gonen, Chunsong Yu, Roberto Avellino, Paulina Chalan, Kiara Freitag, Ido Yofe, Vladimir Yutkin, Pierre Boyeau, Can Ergen, Justin Hong, Kfir Mazuz, Yuxiao Liu, Kangming Chen, Rony Dahan, Marcin Kortylewski, Nir Yosef, Assaf Weiner, Ido Amit

Issue&Volume: 2025-04-10

Abstract: Tumor-associated macrophages (TAMs) are key mediators of tumor immune evasion. However, their regulatory circuits and checkpoints are partially understood. Here, we generated a TAM regulatory network by integrating human tumors single-cell RNA sequencing (scRNA-seq) data with a dedicated CRISPR screen. Using a deep generative model, we constructed a gene perturbation network linking individual candidates with prototypical TAM functions. We identified Zeb2 as the master regulator of TAM programs, orchestrating suppression of type-I interferon response and antigen presentation alongside activation of immune suppression programs. Genetic ablation of ZEB2 reprograms TAM function and identity on the chromatin, RNA, and protein levels. In macrophage-rich human tumors, ZEB2 expression is associated with poor prognosis. Selective Zeb2 in vivo targeting reprograms TAMs and mobilizes systemic T cell responses, achieving robust tumor clearance. Overall, our study generates a detailed roadmap of TAM gene circuits and identifies ZEB2 as a master switch with therapeutic potential.

DOI: 10.1016/j.ccell.2025.03.021

Source: https://www.cell.com/cancer-cell/abstract/S1535-6108(25)00122-9