2. Academic Validation
  3. Transcription factor Zhx2 is a checkpoint that programs macrophage polarization and antitumor response

Transcription factor Zhx2 is a checkpoint that programs macrophage polarization and antitumor response

  • Cell Death Differ. 2023 Aug 15. doi: 10.1038/s41418-023-01202-4.
Siyu Tan # 1 2,  Zehua Wang # 2 3,  Na Li 2,  Xiaowei Guo 2,  Yankun Zhang 2,  Hongxin Ma 2 4,  Xueqi Peng 2,  Ying Zhao 2,  Chunyang Li 5,  Lifen Gao 2,  Tao Li 1,  Xiaohong Liang 6,  Chunhong Ma 7
Affiliations

Affiliations

  • 1 Department of General Surgery, Qilu Hospital, Shandong University, Jinan, China.
  • 2 Key Laboratory for Experimental Teratology of Ministry of Education, Key Laboratory of Infection and Immunity of Shandong Province and Department of Immunology, School of Basic Medical Sciences, Qilu Hospital, Cheeloo Medical College of Shandong University, Jinan, Shandong, China.
  • 3 Department of Clinical Laboratory, Qilu Hospital, Shandong University (Qingdao), Qingdao, China.
  • 4 Department of Clinical Laboratory, Shandong Cancer Hospital and Institute, Shandong First Medical University, and Shandong Academy of Medical Sciences, Jinan, China.
  • 5 Key Laboratory for Experimental Teratology of Ministry of Education, Department of Histology and Embryology, School of Basic Medical Sciences, Cheeloo Medical College of Shandong University, Jinan, Shandong, China.
  • 6 Key Laboratory for Experimental Teratology of Ministry of Education, Key Laboratory of Infection and Immunity of Shandong Province and Department of Immunology, School of Basic Medical Sciences, Qilu Hospital, Cheeloo Medical College of Shandong University, Jinan, Shandong, China. [email protected].
  • 7 Key Laboratory for Experimental Teratology of Ministry of Education, Key Laboratory of Infection and Immunity of Shandong Province and Department of Immunology, School of Basic Medical Sciences, Qilu Hospital, Cheeloo Medical College of Shandong University, Jinan, Shandong, China. [email protected].
  • # Contributed equally.
PMID: 37582865 DOI: 10.1038/s41418-023-01202-4
Abstract

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.

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