Lactylation of PD-L1 by a lactyltransferase HAT1 dictates its protein stability and tumor immune evasion
Lysine lactylation regulates protein fate and function across diverse biological processes. While PD-L1 has been widely studied posttranslationally, the role of its lactylation and the responsible enzyme have remained poorly studied. Here, we identify histone acetyltransferase 1 (HAT1) as a lactyltransferase that catalyzes programmed cell death ligand 1 (PD-L1) lactylation at residues K75 and K178 within its extracellular domain, thereby enhancing PD-L1 stability. Mechanistically, this glycosylation-dependent modification protects PD-L1 from endoplasmic reticulum (ER)-associated degradation and promotes ER-to-Golgi trafficking. Targeting PD-L1 lactylation by HAT1 knockdown, mutation of the lactylation sites or HAT1-PD-L1-interferring peptides suppresses tumor progression and enhances anti-PD-1 therapy efficacy. Clinically, lactylated PD-L1 strongly correlates with tumor progression. Together, these findings establish HAT1-mediated PD-L1 lactylation as a key mechanism of immune evasion and suggest that targeting this pathway could improve cancer immunotherapy outcomes.
Authors
- Yibi Zhang (ORCID: https://orcid.org/0000-0002-3232-9236)
- Siyuan Jiang (ORCID: https://orcid.org/0000-0002-0684-789X)
- Man Shang (ORCID: https://orcid.org/0000-0003-1788-2284)
- Yongbo Pan (ORCID: https://orcid.org/0000-0002-3850-7304)
- Chenbo Ji
- Shuguang Tan (ORCID: https://orcid.org/0000-0002-2599-4959)
- Shan Gao (ORCID: https://orcid.org/0000-0003-1950-0729)
- Yinmin Gu (ORCID: https://orcid.org/0000-0001-9825-5447)
- Xujie Zhao
- Xiaofeng Zhu
- C P Zhang
- Ya Wen (ORCID: https://orcid.org/0000-0001-8621-8016)
- Xiaohui Yang (ORCID: https://orcid.org/0000-0001-5175-5209)
- Yiwen Chen
- Xuemei Jia
Institutions
- Jiangsu University (CN)
- Guizhou University (CN)
- Nanjing Maternity and Child Health Care Hospital (CN)
- Xuzhou Cancer Hospital (CN)
- Fertility Medical Group (BR)
- Xuzhou Central Hospital (CN)
- Second Affiliated Hospital of Zhejiang University (CN)
Publication Details
- Journal
- Proceedings of the National Academy of Sciences
- Published
- 2026-05-27
- DOI
- https://doi.org/10.1073/pnas.2537490123
- Primary Topic
- Cancer Immunotherapy and Biomarkers
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- National Natural Science Foundation of China
- China Postdoctoral Science Foundation
- Natural Science Foundation of Jiangsu Province
- Basic Research Program of Jiangsu Province
- National Key Research and Development Program of China
- Fundamental Research Funds for the Central Universities