Multimodal clinical parameters-based immune status associated with the prognosis in patients with hepatocellular carcinoma

Table 5 Impact on immune microenvironment and prognosis of immunohistochemical markers in hepatocellular carcinoma

Category	Marker	Impact on immune microenvironment	Impact on prognosis	Clinical decision-guiding value
Immunosuppressive	PD-L1/PD-1	Induces T-cell exhaustion via PD-1/PD-L1	High expression: Improved objective response rate and disease control rate to PD-1/PD-L1 inhibitors in advanced HCC	Predictive: Supports the selection of PD-1/PD-L1 inhibitor therapy
	CTLA-4	Blocks CD28- B7 costimulation; expands Tregs	High expression: Increased Treg infiltration and poorer OS	Emerging target: Informs the potential for combination immunotherapy strategies
	TIM-3	Triggers T-cell apoptosis; polarizes M2 macrophages	Co-expression with PD-1: Reduced OS	Mechanistic insight: Supports the development of dual-targeting approaches
Proliferation/invasion	Ki-67	Drives cell-cycle dysregulation	High expression (> 30%): Increased tumor recurrence after liver transplantation	Prognostic: May necessitate more intensive post-transplant surveillance
	MMP-2/9	Degrades ECM; recruits MDSCs	High expression: Promotes HCC invasion and metastasis	Prognostic: Indicates high risk of metastasis, warranting comprehensive staging and follow-up
Angiogenic	DCP (PIVKA-II)	Activates VEGF pathway	Post-treatment decline: Predicts improved clinical outcomes	Monitoring: Serves as a surrogate biomarker for monitoring treatment efficacy in AFP-negative HCC
	GP73	Promotes angiogenesis via mTOR-VEGFA	High expression: Poor prognosis in HCC	Prognostic: Identifies patients with aggressive disease for more aggressive management
Metabolic dysregulation	AFP	Suppresses DC maturation and contributes to immunosuppression	Baseline AFP < 400 ng/mL or an early AFP response (≥ 75% decline): Predicts improved OS	Predictive and monitoring: Key for patient selection and early efficacy assessment in atezolizumab + bevacizumab therapy
	AFP-L3	Evades variant associated with immune evasion	AFP-L3% > 10%: Poorer OS and higher early recurrence rates	Risk stratification: Identifies high-risk patients for adjuvant therapy or closer monitoring
Tumor suppressor dysfunction	P53	Mutant recruits MDSCs; secretes immunosuppressive cytokines	Drives HCC progression and immunosuppression: Predicts poor prognosis	Prognostic: Suggests high-risk biology, informing the need for adjuvant therapy or enrollment in clinical trials
Immune infiltration	CD3+ T-cells	Mediates antitumor immunity (TCR-MHC)	High intratumoral density: Favorable prognostic factor for improved RFS	Prognostic: May support de-escalation of aggressive therapy in early-stage disease
Emerging targets	LAG-3	Binds MHC-II; synergizes with PD-1 to exhaust T-cells	High expression: Links to inferior RFS and OS	Emerging target: Informs the rationale for combining anti-PD-1 with anti-LAG-3 therapy

PD-L1: Programmed death-ligand 1; PD-1: Programmed cell death protein 1; CTLA-4: Cytotoxic T-lymphocyte-associated protein 4; TIM-3: T-cell immunoglobulin and mucin-domain containing-3; MMP-2/9: Matrix metalloproteinase-2/9; DCP: Des-gamma-carboxy prothrombin; PIVKA-II: Protein induced by vitamin K absence/antagonist-II; Ki-67: Kiel-67; GP73: Golgi protein 73; AFP: Alpha-fetoprotein; AFP-L3: Alpha-fetoprotein L3 fraction; P53: Tumor protein p53; LAG-3: Lymphocyte-activation gene 3; Tregs: Regulatory T cells; ECM: Extracellular matrix; MDSCs: Myeloid-derived suppressor cells; VEGF: Vascular endothelial growth factor; mTOR: Mammalian target of rapamycin; VEGFA: Vascular endothelial growth factor A; DC: Dendritic cell; TCR: T-cell receptor; MHC: Major histocompatibility complex; MHC-II: Major histocompatibility complex class II; OS: Overall survival; HCC: Hepatocellular carcinoma; RFS: Recurrence-free survival.