Post-translational modifications in hepatocellular carcinoma: Linking senescence, metabolic reprogramming, and immune evasion for therapeutic innovation

Abstract

Hepatocellular carcinoma remains a leading cause of cancer mortality. Although immune checkpoint inhibitors have improved outcomes for a subset of patients, primary and acquired resistance are common. Post-translational modifications (PTMs) provide a rapid and reversible regulatory layer that links oncogenic signaling, metabolism, and chromatin state to cellular senescence and the tumor microenvironment. Here we synthesize evidence showing how ubiquitination, phosphorylation, acetylation, methylation, SUMOylation, O-GlcNAcylation, and lactylation modulate core senescence programs (p53/retinoblastoma protein, DNA-damage response) and the senescence-associated secretory phenotype, thereby shaping myeloid recruitment, T-cell dysfunction, and immune evasion in hepatocellular carcinoma. We further discuss how metabolism-coupled PTMs rewire glycolysis-epigenetics crosstalk and generate spatially confined senescence-metabolic-immune niches that can be resolved by single-cell and spatial multi-omics. The current evidence base is dominated by mechanistic studies and correlative clinical datasets, underscoring the need for prospective validation and standardized PTM/senescence biomarkers. Finally, we propose a sequential “induce-remodel-clear” therapeutic concept in which senescence induction is paired with PTM-targeted modulation and immune or senolytic clearance to improve response durability.

Keywords: Hepatocellular carcinoma; Post-translational modifications; Cellular senescence; Tumor immune microenvironment; Metabolic reprogramming; Immunotherapy; Single-cell multi-omics; Spatial transcriptomics; Therapy resistance; Precision medicine

Core Tip: Posttranslational modifications (PTMs) constitute a dynamic regulatory network that critically shapes cellular senescence and the immunosuppressive microenvironment in hepatocellular carcinoma. Key metabolism-linked PTMs such as O-GlcNAcylation and histone lactylation couple glycolytic reprogramming with epigenetic remodeling, driving therapy resistance and immune evasion. Emerging single-cell and spatial multi-omics reveal spatially organized senescence-immune-metabolic niches, providing a basis for multidimensional stratification. This review proposes a sequential “induce-remodel-clear” therapeutic framework, integrating precise senescence induction, PTM-targeted modulation, and enhanced immune clearance to overcome resistance and advance precision hepatocellular carcinoma therapy.