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

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.