Lactylation of PD-L1 by a lactyltransferase HAT1 dictates its protein stability and tumor immune evasion
Abstract
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.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (15)
Man Shang
Department of Gynecology, Women’s Hospital of Nanjing Medical University (Nanjing Women and Children’s Healthcare Hospital)
Xujie Zhao
Zhongda Hospital, School of Life Sciences and Technology, Advanced Institute for Life and Health, Southeast University
Yibi Zhang
School of Biomedical Engineering (Suzhou), Division of Life Sciences and Medicine, University of Science and Technology of China
Chang Zhang
Xiaohui Yang
Department of Gynecology, Women’s Hospital of Nanjing Medical University (Nanjing Women and Children’s Healthcare Hospital)
Ya Wen
MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, State Key Laboratory of Anti-Infective Drug Discovery and Development, Guangdong Basic Research Center of Excellence for Functional Molecular Engineering, School of Chemistry
Xiaofeng Zhu
Yiwen Chen
Yinmin Gu
Zhongda Hospital, Medical School, Advanced Institute for Life and Health, Southeast University
Yongbo Pan
Zhongda Hospital, School of Life Sciences and Technology, Advanced Institute for Life and Health, Southeast University
Siyuan Jiang
Zhongda Hospital, School of Life Sciences and Technology, Advanced Institute for Life and Health, Southeast University
Shuguang Tan
Innovative Vaccine and Immunotherapy Research Center, The Second Affiliated Hospital, Zhejiang University School of Medicine
Xuemei Jia
Department of Gynecology, Women’s Hospital of Nanjing Medical University (Nanjing Women and Children’s Healthcare Hospital)
Chenbo Ji
Nanjing Medical Key Laboratory of Female Fertility Preservation and Restoration
Shan Gao