TY  - JOUR
T1  - The Emerging Role of the Lactylation-autophagy Axis in Hepatocellular Carcinoma: A Metabolic-epigenetic Driver of Tumor Immune Remodeling 
AU  - Ning, Yinkuan
AU  - Song, Youai
AU  - Xie, Longhui
AU  - Yang, Yang
AU  - Zhou, Cila
JF  - Journal of Clinical and Translational Hepatology
VL  - 
IS  - 000
SN  - 2310-8819
SP  - 
EP  - 
Y1  - 2026-10-19
DO  - 10.14218/JCTH.2026.00385
UR  - https://www.xiahepublishing.com/2310-8819/JCTH-2026-00385
AB  - Hepatocellular carcinoma (HCC) exhibits profound metabolic reprogramming, with enhanced aerobic glycolysis and excess lactate production as defining features. Lactate, once regarded simply as a metabolic byproduct, is now recognized as a powerful epigenetic driver through lysine lactylation, while tumor cells co-opt autophagy to endure metabolic stress. Although traditionally investigated as separate hallmarks of cancer, growing evidence points to their functional intersection. Here, we propose the concept of a coordinated “lactylation-autophagy axis” and clarify its role in remodeling the tumor immune microenvironment. Within this integrated metabolic-epigenetic-proteostatic network, lactate-induced histone lactylation, such as H3K18la, exerts transcriptional control over tumor-associated macrophages, shifting them toward an immunosuppressive M2-like state. Excess extracellular lactate and robust autophagic adaptation cooperate to impair the effector functions of CD8+ T cells and natural killer cells, while providing regulatory T cells with metabolic advantages. We further explore the bidirectional crosstalk within this axis: lactate modulates autophagic flux, potentially through mTOR signaling and non-histone lactylation of autophagy-related proteins (e.g., VPS34, TFEB), whereas autophagy in turn regulates intracellular metabolite pools and lactylation substrates. Notably, several nodes, particularly non-histone lactylation of VPS34, TFEB, and mTOR (K921), have been demonstrated mainly in non-HCC systems; we therefore grade each mechanism as confirmed in HCC, extrapolated from other systems, or hypothetical. This proposed self-reinforcing axis may sustain tumor plasticity, contribute to immune evasion and immunotherapy resistance, and we discuss rational combinatorial strategies—combined targeting of lactate metabolism, lactylation machinery, and autophagic pathways—to sensitize advanced HCC to immune checkpoint blockade.