PD-L1 Lactylation Overturned the Understanding of Lactylations in Hepatocellular Carcinoma
DOI:
https://doi.org/10.61173/fxs2y528Keywords:
PD-L1 lactylation, Hepatocellular carcinoma, Immune evasion, Tumor metabolismAbstract
Hepatocellular carcinoma (HCC) is a leading cause of cancer mortality, and tumor immune evasion mediated by the PD-1/PD-L1 checkpoint axis constitutes a critical therapeutic barrier. Accumulating evidence demonstrates that aberrant tumor metabolism, particularly lactate accumulation and the associated post-translational modification of lysine lactylation (Kla), can modulate PDL1 expression and function. Recent studies reveal that lysine lactylation modulates PD-L1 through multifaceted mechanisms: histone lactylation at the PD-L1 gene promoter can elevate PD-L1 transcription; lactylationdriven upregulation of factors such as major vault protein (MVP) inhibits PD-L1 proteasomal degradation, increasing its stability; and PD-L1 itself is subject to direct lactylation. Notably, lactylation of PD-L1 at lysine 189 (K189) has been shown to abrogate its nuclear translocation; loss of this modification enables vimentin-mediated nuclear translocation of PD-L1, which in turn promotes tumor progression and metastatic dissemination by triggering de novo cholesterol biosynthesis. These insights underscore a novel link between metabolic reprogramming and immune checkpoint regulation, suggesting that targeting the lactylation pathway in a context-dependent manner across distinct tumor stages may optimize therapeutic outcomes in HCC.
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