| First Author | Sheban F | Year | 2025 |
| Journal | Cancer Cell | Volume | 43 |
| Issue | 7 | Pages | 1227-1241.e11 |
| PubMed ID | 40215981 | Mgi Jnum | J:386355 |
| Mgi Id | MGI:8222200 | Doi | 10.1016/j.ccell.2025.03.021 |
| Citation | Sheban F, et al. (2025) ZEB2 is a master switch controlling the tumor-associated macrophage program. Cancer Cell 43(7):1227-1241.e11 |
| abstractText | 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. |
