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

Table 1 Major post-translational modification classes linking senescence regulation to immune features in hepatocellular carcinoma

PTM class	Key regulators/substrates (examples)	Primary senescence axis	Immune/TME-relevant effect	Evidence in HCC (typical)	Translational implication	Ref.
Ubiquitination/deubiquitination	MDM2-p53; NEDD4-PTEN; USP family	Checkpoint control (p53/pRb), senescence escape	Shapes antigen presentation and myeloid/T-cell balance via p53–inflammation and PI3K-AKT signaling	Strong mechanistic; clinical links mainly correlative	Target E3/DUBs to stabilize p53 and sensitize to ICI or senolytics	[141-143]
SUMOylation/deSUMOylation	SUMO1/2/3; PIAS; SENP enzymes	Stress signaling; transcription factor activity	Can promote immune evasion through TF reprogramming and inflammatory signaling	Mechanistic; limited prospective clinical validation	SENP/PIAS modulation as an immuno-sensitizing adjunct	[144,145]
Acetylation/deacetylation	p300/CBP; SIRT1/2; HDACs	p53 activity; chromatin accessibility; SASP tuning	Controls inflammatory transcription and exhaustion programs (NF-κB, STATs)	Strong in vitro/in vivo; growing clinical correlative data	HDAC/SIRT targeting to balance senescence induction vs chronic SASP; combine with IO	[146-148]
O-GlcNAcylation	OGT/OGA; YBX1; c-Myc (examples)	Metabolism–chromatin coupling; senescence tolerance	Links nutrient state to immune suppression (myeloid bias, T-cell dysfunction)	Emerging mechanistic; early clinical correlative signals	OGT/OGA inhibition to disrupt metabolic tolerance and recondition TME	[149-151]
Histone lactylation	Lactate; p300; H3K18 La (marker)	Epigenetic remodeling of senescence and stemness programs	Promotes pro-tumor inflammation and immune suppression in lactate-rich niches	Emerging; evidence largely preclinical/omics	Target lactate production/transport or lactylation writers in combination regimens	[152,153]
Histone/non-histone methylation	EZH2; SETD2; KMT/KDM enzymes	Stable chromatin states; senescence maintenance/escape	Regulates antigen presentation and myeloid polarization via epigenetic programs	Mechanistic + correlative cohorts; limited intervention trials in HCC	Epigenetic therapy to restore immune visibility and constrain senescence escape	[154-156]

PTM: Posttranslational modification; TME: Tumor microenvironment; HCC: Hepatocellular carcinoma; MDM2: Mouse double minute 2 homolog; p53: Tumor protein p53; NEDD4: Neural precursor cell expressed developmentally downregulated protein 4; PTEN: Phosphatase and tensin homolog; USP: Ubiquitin-specific protease; pRb: Retinoblastoma protein; PI3K: Phosphoinositide 3-kinase; AKT: Protein kinase B; E3: E3 ubiquitin-protein ligase; DUB: Deubiquitinating enzyme; ICI: Immune checkpoint inhibitor; SUMO: Small ubiquitinlike modifier; PIAS: Protein inhibitor of activated signal transducer and activator of transcription; SENP: Sentrin/small ubiquitin like modifier-specific protease; TF: Transcription factor; p300: Histone acetyltransferase p300; CBP: CREB-binding protein; SIRT: Sirtuin; HDAC: Histone deacetylase; SASP: Senescence-associated secretory phenotype; NF-κB: Nuclear factor-κB; STAT: Signal transducer and activator of transcription; IO: Immunotherapy; OGT: O-GlcNAcylation transferase; OGA: O-GlcNAcase; YBX1: Y-box binding protein 1; c-Myc: Cellular myelocytomatosis oncogene; H3K18 La: Histone H3 lysine 18 lactylation; EZH2: Enhancer of zeste homolog 2; SETD2: SET domain containing 2; KMT: Lysine methyltransferase; KDM: Lysine demethylase.

Table 2 Combined senescence-post-translational modification-immunotherapy strategy in hepatocellular carcinoma based on an “induce-remodel-clear” framework

Clinical stage	Step 1: Induce senescence	Step 2: Remodel PTM/metabolism/SASP (emphasizing immune regulation)	Step 3: Immune/senolytic clearance	Key monitoring indicators (including immune infiltration and function)	Potential beneficiary population	Ref.
Pre-systemic therapy (prior to IO ± anti-VEGF initiation)	TACE/ablation or short-course TKI ± local radiotherapy to induce TIS	Anti-VEGF to improve vascular perfusion and T-cell infiltration; low-intensity JAK/STAT or NF-κB inhibition to reduce IL-6/IL-8type SASP; exploratory OGT/MCT modulation to alleviate metabolic suppression	Initiate PD-1/PD-L1 monoclonal antibody; add shortcourse senolytics during stable phase	Tissue: P16/p21, γH2AX, Ki-67, H3K18 La, O-GlcNAc; spatial immune: CD8+ T/Treg/MDSC/TAM spatial distribution; plasma: IL-6/IL-8/VEGF, lactate; dynamic CSS/SRS	Child-Pugh A patients with prominent vascular abnormalities, myeloid enrichment, and partially inflamed TIME	[26,192-194]
Post-TACE/radiotherapy/ablation (TIS window)	Local therapy to induce definite TIS (elevated p16/p21, γH2AX)	Short-course ATR/mTORC1 inhibition to restrict repair; JAK/STAT or NF-κB inhibition to reduce pro-tumor SASP; LDH/MCT inhibition to lower lactate and lactylation	Intensify PD-1/PD-L1 therapy during TIS peak; experimental addition of senolytics	Paired biopsies: Senescence markers, SASP profile, CD8+ T-cell re-infiltration; imaging: Necrotic area and “inflammatory rim”; dynamic cytokine profiling	Patients with moderate-to-high recurrence risk after local therapy, preserved liver function, and accessible tissue sampling	[85,195]
TKI or IO maintenance phase with acquired resistance	Long-term TKI/IO selects reversible senescence/drug-resistant clones	MDM2 inhibition + p300/CBP modulation to stabilize p53-dependent senescence; OGT/MCT and SUMO pathway targeting to reshape SASP and metabolism	Escalate IO regimen (e.g., PD-1 + CTLA-4) or explore NKG2D-CAR T; short-course senolytics to eliminate persistent senescent clones	PTM: O-GlcNAc, H3K18 La, EZH2; immune phenotype: PD-L1 glycosylation, TCR clonality, T cell exhaustion markers; metabolism: Lactate, glycolysis score	Patients initially responsive to IO/TKI who later progress slowly, with high senescence burden, immunosuppressive SASP, and strong metabolic reprogramming	[103,184,196]
Perioperative/early-intermediate HCC (neoadjuvant/adjuvant phase)	Short-course neoadjuvant TACE/radiotherapy or CDK4/6 inhibitor-induced TIS; or gentle postoperative senescence induction	Low-dose JAK/STAT/NF-κB inhibition to balance regenerative-phase SASP; moderate OGT/MCT inhibition to avoid immunosuppressive niche formation	Medium- to long-term PD-1/PD-L1 ± anti-VEGF as immune surveillance; short-course senolytic trial in very-high-risk subgroups	Resection specimens: CSS/SRS, PTM (O-GlcNAc, H3K18 La, EZH2), spatial immune mapping; follow-up: SASP factors, ctDNA, recurrence patterns	BCLC early-intermediate stage, high-risk of recurrence post-resection/transplantation (MVI, satellite nodules, molecular high-risk), with preserved liver function	[45,197,198]

PTM: Post-translational modification; SASP: Senescence-associated secretory phenotype; HCC: Hepatocellular carcinoma; IO: Immunotherapy; TACE: Transarterial chemoembolization; TKI: Tyrosine kinase inhibitor; TIS: Therapy-induced senescence; VEGF: Vascular endothelial growth factor; JAK: Janus kinase; STAT: Signal transducer and activator of transcription; NF-κB: Nuclear factor-κB; IL-6: Interleukin-6; IL-8: Interleukin-8; OGT: O-GlcNAcylation transferase; MCT: Monocarboxylate transporter; PD-1: Programmed cell death protein 1; PD-L1: Programmed death-ligand 1; H3K18 La: Histone H3 lysine 18 lactylation; Treg: Regulatory T cell; MDSC: Myeloid-derived suppressor cell; TAM: Tumor-associated macrophage; TIME: Tumor immune microenvironment; CSS: Cellular senescence score; SRS: Senescence-related signature; γH2AX: Phosphorylated histone H2AX; Ki-67: Marker of proliferation Ki-67; ATR: Ataxia telangiectasia and Rad3-related; mTORC1: Mechanistic target of rapamycin complex 1; LDH: Lactate dehydrogenase; CBP: CREB-binding protein; SUMO: Small ubiquitinlike modifier; CTLA-4: Cytotoxic T-lymphocyte-associated protein 4; NKG2D: Natural killer group 2D; CAR T: Chimeric antigen receptor T cell; EZH2: Enhancer of zeste homolog 2; TCR: T cell receptor; CDK4/6: Cyclin-dependent kinase 4/6; MVI: Microvascular invasion; BCLC: Barcelona Clinic Liver Cancer; ctDNA: Circulating tumor DNA.