2. Academic Validation
  3. TGF-β1 induces autophagy and mediates the effect on macrophages differentiation in primary liver cancer

TGF-β1 induces autophagy and mediates the effect on macrophages differentiation in primary liver cancer

  • Int Immunopharmacol. 2025 Jun 5:157:114799. doi: 10.1016/j.intimp.2025.114799.
Chao Liu 1,  Mingjie Li 2,  Lichao Liu 2,  Qian Xu 2,  Linlin Zheng 2,  Cailing Wu 3,  Jinghua Ren 4,  Tao Zhang 5,  Haihong Wang 6,  Zhenyu Lin 7
Affiliations

Affiliations

  • 1 Yichang Central People's Hospital, The First College of Clinical Medical Science, China Three Gorges University, Yichang, People's Republic of China.
  • 2 Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China; Institute of Radiation Oncology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China.
  • 3 Faculty of Medicine, JiuJiang University, Jiujiang, People's Republic of China.
  • 4 Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China; Institute of Radiation Oncology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China; Hubei Key Laboratory of Precision Radiation Oncology, Wuhan, People's Republic of China.
  • 5 Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China; Institute of Radiation Oncology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China. Electronic address: taozhangxh@hust.edu.cn.
  • 6 Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China; Institute of Radiation Oncology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China. Electronic address: d201881520@hust.edu.cn.
  • 7 Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China; Institute of Radiation Oncology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China. Electronic address: whxhlzy@hust.edu.cn.
PMID: 40339499 DOI: 10.1016/j.intimp.2025.114799
Abstract

Background: Tumor-associated macrophages (TAMs) are closely associated with tumor development and patient outcomes due to their plasticity and polarization capacity. Several distinct TAMs have been proposed, but a complete understanding of heterogeneity and differentiation spectrum of macrophage in human primary liver Cancer remains elusive.

Methods: Deep single-cell RNA Sequencing (scRNA-seq) data from 19 primary liver Cancer patients were used to profile the transcriptomes of TAMs in liver Cancer. Ingenuity pathway analysis (IPA) and in vitro experiments were used to explore possible mechanisms responsible for related signaling pathways altered at the transcriptional level. Finally, we analyzed the relationship between the abundance of the TAMs and the survival outcomes of the 428 patients in the Cancer Genome Atlas (TCGA).

Results: Transcriptional profiles allowed us to identify four distinct TAMs cell subsets based on molecular and functional properties and to reconstruct their developmental trajectory. Specifically, TAM_c4 was preferentially enriched and potentially expanded in the advanced-stage patients or those receiving immune checkpoint blockade therapy (ICT). Gene pathway analysis revealed aberrant TGFB1 activation in TAM_c4, which was experimentally confirmed to drive TAM phenotypic transitions via Autophagy signaling. High abundance of TAM_c4 is found to be related to a short survival time and low abundance of CD8+ T cells in primary liver cancers.

Conclusions: This integrated transcriptome compendium and experimental validation offer both mechanistic insights and a resource for understanding TAM heterogeneity in primary liver cancers.

Keywords

Phenotypic transition; Primary liver cancer; Single-cell RNA sequencing; TGFB1; Tumor-associated macrophages.

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