Programmed death-ligand 1 (PD-L1) (PD-L1)

PD-L1 lactylation is a recently characterized post-translational modification (PTM) where a lactyl group is covalently attached to lysine residues (Kla) of the Programmed death-ligand 1 (PD-L1) protein. In a glycolytic tumor microenvironment, high levels of lactate drive this modification, primarily mediated by the lactyltransferase p300 (EP300), which stabilizes the PD-L1 protein by preventing its lysosomal or proteasomal degradation. This enhanced stability increases the density of PD-L1 on the tumor cell surface, significantly contributing to immune evasion and resistance to standard immunotherapy. Beyond direct protein modification, lactate-induced histone lactylation (such as H3K18la) acts as an epigenetic regulator to upregulate the transcription of the CD274 gene, further increasing PD-L1 abundance. Targeting the lactylation pathway—either through direct inhibition of the modification process or by metabolic reprogramming of the tumor microenvironment—represents a promising therapeutic frontier. This approach aims to sensitize tumors to immune checkpoint inhibitors and overcome the primary or acquired resistance often observed in highly glycolytic malignancies.

Other names

CD274B7-H1B7 homolog 1Lactylated PD-L1PD-L1 Lysine Lactylation (Kla)

Conventional PD-L1 inhibitors block the binding between PD-L1 and PD-1 to restore T-cell-mediated anti-tumor immunity. Emerging strategies targeting PD-L1 lactylation aim to inhibit the 'writer' enzyme p300 (EP300), reduce lactate production via LDH inhibitors, or block lactate transport via MCT1/4 inhibitors to prevent the stabilization and accumulation of PD-L1 on the cell surface.