Lactylation of PD-L1 by a lactyltransferase HAT1 dictates its protein stability and tumor immune evasion
Menée à l'aide de lignées cellulaires, de modèles murins ainsi que d'échantillons tumoraux issus de patients atteints d'un cancer du rein ou de patientes atteintes d'un cancer de l'ovaire, cette étude met en évidence un mécanisme par lequel la lactylation du ligand PD-L1 par la lactyltransférase HAT1 favorise l'échappement immunitaire et la progression de la tumeur
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.
Proceedings of the National Academy of Sciences , résumé, 2026