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Related Experiment Video

Updated: May 14, 2025

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

Fadi Sheban1, Truong San Phan1, Ken Xie1

  • 1Department of Systems Immunology, Weizmann Institute of Science, Rehovot 7610001, Israel.

Cancer Cell
|April 11, 2025
PubMed
Summary

Tumor-associated macrophages (TAMs) suppress immune responses. Our study reveals Zeb2 as a master regulator of TAMs, reprogramming them to enhance anti-tumor immunity and improve patient prognosis.

Keywords:
CRISPRTAM reprogrammingZeb2cancer immunologycancer immunotherapydeep generative modelingregulatory networksingle cell genomicssystems immunolgytumor-associated macrophage

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Area of Science:

  • Immunology
  • Cancer Biology
  • Genomics

Background:

  • Tumor-associated macrophages (TAMs) are crucial for tumor immune evasion.
  • The regulatory mechanisms governing TAM functions remain incompletely understood.

Purpose of the Study:

  • To elucidate the regulatory circuits of TAMs.
  • To identify key regulators of TAM function and therapeutic targets.

Main Methods:

  • Integration of human tumor single-cell RNA sequencing (scRNA-seq) data with CRISPR screening.
  • Utilized a deep generative model to construct a gene perturbation network.
  • Investigated Zeb2's role through genetic ablation and in vivo targeting.

Main Results:

  • Identified Zeb2 as the master regulator of TAM programs, controlling immune suppression and antigen presentation.
  • Demonstrated that Zeb2 ablation reprograms TAMs at multiple molecular levels.
  • Found Zeb2 expression correlates with poor prognosis in human tumors.
  • Showed Zeb2 targeting in vivo reprograms TAMs and enhances systemic T cell responses for tumor clearance.

Conclusions:

  • Zeb2 acts as a master switch for TAM regulatory circuits.
  • Targeting Zeb2 holds significant therapeutic potential for reprogramming TAMs and improving anti-tumor immunity.