AEBP1 drives fibroblast-mediated T cell dysfunction in tumors
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.
Authors
- Ziying Yi (ORCID: https://orcid.org/0000-0002-5462-5212)
- Linling Wu (ORCID: https://orcid.org/0000-0001-6440-204X)
- Jingyuan Wan (ORCID: https://orcid.org/0000-0002-1773-6474)
- Jiazhou Liu (ORCID: https://orcid.org/0000-0003-4541-0233)
- Hongzhong Li (ORCID: https://orcid.org/0000-0003-1136-5235)
- Jiazheng Sun (ORCID: https://orcid.org/0000-0003-2512-7887)
- Jiakui Li (ORCID: https://orcid.org/0000-0002-6065-6648)
- Yushen Wu (ORCID: https://orcid.org/0000-0002-6122-2593)
- Jiefeng Huang (ORCID: https://orcid.org/0000-0003-3021-3333)
- Daqiang Song
- Xiaoyu Wang (ORCID: https://orcid.org/0000-0003-2933-7582)
- Xiang Zhang (ORCID: https://orcid.org/0000-0003-1003-9892)
- Chong Li (ORCID: https://orcid.org/0000-0002-2862-1357)
- Li Zhang (ORCID: https://orcid.org/0000-0002-3617-2627)
- Guosheng Ren (ORCID: https://orcid.org/0000-0002-6416-8967)
- Yongxue Zhu (ORCID: https://orcid.org/0009-0003-9657-7620)
- Huimin Du (ORCID: https://orcid.org/0000-0002-9330-0488)
- Yuxian Wei
- Li Fan (ORCID: https://orcid.org/0000-0002-2252-9840)
Institutions
- Jinan University (CN)
- Southern University of Science and Technology (CN)
- The Affiliated Yongchuan Hospital of Chongqing Medical University (CN)
- Southern Medical University Shenzhen Hospital (CN)
- Shenzhen Second People's Hospital (CN)
- Chongqing Dazu District People's Hospital (CN)
- Chongqing Medical University (CN)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-09-01
- DOI
- https://doi.org/10.1038/s41467-025-63659-w
- Citations
- 3
- Primary Topic
- Cancer Immunotherapy and Biomarkers
- Type
- article
- Field-Weighted Citation Impact
- 3.14
Funders
- National Natural Science Foundation of China
- Chongqing Medical University
- Natural Science Foundation of Chongqing
- Basic and Applied Basic Research Foundation of Guangdong Province