Lactylation of PD-L1 by a lactyltransferase HAT1 dictates its protein stability and tumor immune evasion

• 成果类型: Article
• 署名作者: Shang, Man; Zhao, Xujie; Zhang, Yibi; Zhang, Chang; Yang, Xiaohui; Wen, Ya; Zhu, Xiaofeng; Chen, Yiwen; Gu, Yinmin; Pan, Yongbo; Jiang, Siyuan; Tan, Shuguang; Jia, Xuemei; Ji, Chenbo; Gao, Shan
• 署名单位: Nanjing Medical University; Southeast University - China; Guizhou University; Zhejiang University; Nanjing Medical University; Southeast University - China
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2537490123
• 发表日期: 2026-06-02
• 页码: e2537490123
• 关键词: PD-L1; HAT1; lactylation; immune escape; stabilization

摘要

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.