AEBP1 drives fibroblast-mediated T cell dysfunction in tumors

Xiaoyu Wang, Jie Li, Daqiang Song, Yushen Wu, Jiazhou Liu, Ziying Yi, Jiazheng Sun, Jiefeng Huang, Linling Wu, Xiang Zhang, Jingyuan Wan, Li Zhang, Chong Li, Fan Li, Yuxian Wei, Yong Zhu, Huimin Du, Guosheng Ren () and Hongzhong Li ()
Additional contact information
Xiaoyu Wang: The First Affiliated Hospital of Chongqing Medical University
Jie Li: The First Affiliated Hospital of Chongqing Medical University
Daqiang Song: The First Affiliated Hospital of Chongqing Medical University
Yushen Wu: The First Affiliated Hospital of Chongqing Medical University
Jiazhou Liu: The First Affiliated Hospital of Chongqing Medical University
Ziying Yi: The First Affiliated Hospital of Chongqing Medical University
Jiazheng Sun: The First Affiliated Hospital of Chongqing Medical University
Jiefeng Huang: The First Affiliated Hospital of Chongqing Medical University
Linling Wu: The First Affiliated Hospital of Chongqing Medical University
Xiang Zhang: The First Affiliated Hospital of Chongqing Medical University
Jingyuan Wan: Chongqing Medical University
Li Zhang: Chongqing Medical University
Chong Li: The Affiliated Dazu’s Hospital of Chongqing Medical University
Fan Li: The First Affiliated Hospital of Chongqing Medical University
Yuxian Wei: The First Affiliated Hospital of Chongqing Medical University
Yong Zhu: Chongqing Medical University
Huimin Du: The First Affiliated Hospital of Chongqing Medical University
Guosheng Ren: The First Affiliated Hospital of Chongqing Medical University
Hongzhong Li: The First Affiliated Hospital of Chongqing Medical University

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-63659-w

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