2. Academic Validation
  3. MEF2D-expressing cancer precursors reprogram tissue-resident macrophages to support liver tumorigenesis

MEF2D-expressing cancer precursors reprogram tissue-resident macrophages to support liver tumorigenesis

  • Nat Cancer. 2025 Dec;6(12):1955-1975. doi: 10.1038/s43018-025-01059-1.
Junyu Xiang # 1 2,  Yuanli Ni # 1,  Jiajun Yu # 1 3,  Hui Sun 1,  Zhiyun Gu 1,  Ziyong Li 1,  Tongwang Yang 1,  Juan Feng 1,  Li Su 4,  Limei Liu 1,  Jiatao Li 1,  Jesus Prieto 5 6 7,  Matías A Ávila 5 6 7,  Juanjuan Shan 8,  Na Zhuang 9,  Cheng Qian 10
Affiliations

Affiliations

  • 1 Center for Precision Medicine of Cancer, Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital and Chongqing University School of Medicine, Chongqing, China.
  • 2 Department of Gastroenterology, Chongqing Key Laboratory of Digestive Malignancies, Daping Hospital, Army Medical University, Chongqing, China.
  • 3 Department of Radiation Oncology, Radiation Oncology Key Laboratory of Sichuan Province, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, University of Electronic Science and Technology of China, Chengdu, China.
  • 4 Department of Oncology and Hematology, Chongqing Traditional Chinese Medicine Hospital, Chongqing, China.
  • 5 Hepatology Program, Cima, University of Navarra, Pamplona, Spain.
  • 6 Instituto de Investigaciones Sanitarias de Navarra-IdiSNA, Pamplona, Spain.
  • 7 CIBERehd, Instituto de Salud Carlos III, Madrid, Spain.
  • 8 Center for Precision Medicine of Cancer, Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital and Chongqing University School of Medicine, Chongqing, China. [email protected].
  • 9 Center for Precision Medicine of Cancer, Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital and Chongqing University School of Medicine, Chongqing, China. [email protected].
  • 10 Center for Precision Medicine of Cancer, Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital and Chongqing University School of Medicine, Chongqing, China. [email protected].
  • # Contributed equally.
PMID: 41131393 DOI: 10.1038/s43018-025-01059-1
Abstract

Cancers often originate from precursor cells within an inflamed microenvironment; however, the mechanisms by which these precursors manipulate the niche to promote tumorigenesis remain unclear. By combining single-cell and spatial transcriptomic analyses of precancerous lesions in hepatocellular carcinoma, here we show that elevated myocyte enhancer factor 2D (MEF2D)-expressing Cancer precursors reprogram liver-resident macrophages, Kupffer cells (KCs), to create a growth-supportive environment. MEF2D levels induce an oncogenic and secretory phenotype in these precursors by epigenetic reprogramming, which is crucial for tumor initiation in murine models and human samples. This results in a KC-rich niche through paracrine activation of neuropilin 1 (NRP1) signaling on stem-like KC subtype-2 (KC2), driving its differentiation into KC subtype-1 (KC1)-like cells. Pro-inflammatory KC1s release cytokines, particularly IL-6, to enhance an MEF2D-mediated tumor-promoting program in nearby Cancer precursors. Targeting NRP1 signaling disrupts the KC2-to-KC1-like differentiation and reduces niche inflammation, thereby inhibiting liver tumorigenesis in male mice. Thus, preventing aberrant KC subtype conversion in the precancerous microenvironment is a viable strategy for early Cancer prevention.

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