2. Academic Validation
  3. AEBP1 drives fibroblast-mediated T cell dysfunction in tumors

AEBP1 drives fibroblast-mediated T cell dysfunction in tumors

  • Nat Commun. 2025 Sep 1;16(1):8171. doi: 10.1038/s41467-025-63659-w.
Xiaoyu Wang # 1,  Jie Li # 1 2,  Daqiang Song # 1,  Yushen Wu # 1 3,  Jiazhou Liu # 1,  Ziying Yi 1,  Jiazheng Sun 1,  Jiefeng Huang 1 4,  Linling Wu 1,  Xiang Zhang 1,  Jingyuan Wan 5,  Li Zhang 6,  Chong Li 7,  Fan Li 1,  Yuxian Wei 1,  Yong Zhu 8,  Huimin Du 3,  Guosheng Ren 9,  Hongzhong Li 10
Affiliations

Affiliations

  • 1 Department of Breast and Thyroid Surgery, Chongqing Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
  • 2 Department of Dermatology, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, Guangdong, China.
  • 3 Department of Oncology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
  • 4 Department of Breast Surgery, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, Guangdong, China.
  • 5 Department of Pharmacology, Chongqing Medical University, Chongqing, China.
  • 6 Department of Pathophysiology, Chongqing Medical University, Chongqing, China.
  • 7 Department of Oncology, The Affiliated Dazu's Hospital of Chongqing Medical University, Chongqing, China.
  • 8 Research Institute of Life Sciences, Chongqing Medical University, Chongqing, China.
  • 9 Department of Breast and Thyroid Surgery, Chongqing Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China. rengs726@126.com.
  • 10 Department of Breast and Thyroid Surgery, Chongqing Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China. lihongzhong@cqmu.edu.cn.
  • # Contributed equally.
PMID: 40890191 DOI: 10.1038/s41467-025-63659-w
Abstract

T cell dysfunction enables tumor immune evasion, understanding its mechanism is crucial for improving immunotherapy. Here we show, by RNA-sequencing analysis of human colon adenocarcinoma and triple-negative breast Cancer tissues, that expression of Adipocyte Enhancer-Binding Protein 1 (AEBP1) positively correlates with T cell dysfunction and indicative of unfavorable patient outcomes. Subsequent single-cell RNA Sequencing identifies cancer-associated fibroblasts (CAF) as the primary AEBP1 source. Fibroblast-specific AEBP1 deletion in mice enhances T cell cytotoxicity and suppresses tumor growth. Mechanistically, autocrine AEBP1 binds CKAP4 on CAFs, activating Akt/PD-L1 signaling to drive T cell dysfunction. By molecular-docking-based virtual screening we identify Chem-0199, a drug that disrupts the interaction between AEBP1 and CKAP4, thereby enhancing antitumor immunity. Both genetic and pharmacological AEBP1 inhibition synergize with immune checkpoint blockade in syngeneic models. Our study establishes AEBP1 as a key regulator of CAF-mediated T cell dysfunction and a therapeutic target.

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