IL-17/IL-17RA Axis Facilitates Immune Evasion in Hepatocellular Carcinoma by Upregulating PD-L1 via the NF-κB Pathway.

Authors

Xinyang Li, Ya Wang, Chuan Shen, Ruolan Gu, Mingjie Liu, Ying Xiao, Yuexia Liu, Luyuan Ma, Caiyan Zhao

Published in

Digestive diseases and sciences. Jun 24, 2026. Epub Jun 24, 2026.

Abstract

The immunosuppressive tumor microenvironment in hepatocellular carcinoma (HCC) limits therapeutic efficacy. This study aimed to develop an immune-related signature for risk stratification and to identify key molecules that drive immune evasion.
Transcriptomic data from HCC were analyzed to identify immune-related genes. A prognostic risk signature was constructed using Cox and least absolute shrinkage and selection operator regression and validated in an independent external cohort. Immune cell infiltration, immune checkpoints, and interleukin (IL)-17RA expression were characterized. Serum IL-17 levels were measured in patients with HCC, patients with cirrhosis, and healthy controls. Mechanistic studies included analyses of cell proliferation, programmed death-ligand 1 (PD-L1) expression, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activation, and the effects of IL-17RA knockdown.
A six-gene risk signature stratified patients into high- and low-risk groups. The high-risk group exhibited poorer prognosis and a more immunosuppressive microenvironment. External validation confirmed model robustness, with the risk score as an independent prognostic factor (multivariable Cox, P < 0.05). IL-17RA was overexpressed in HCC and correlated with poor prognosis, immune checkpoints, and M2 macrophage infiltration. Serum IL-17 levels were elevated in patients with HCC, had diagnostic value (area under the curve [AUC] = 0.738), and predicted vascular invasion (AUC = 0.891). Mechanistically, IL-17 activated NF-κB, increased p-p65, induced p65 nuclear translocation, upregulated PD-L1, and stimulated HCC cell proliferation. Pharmacological NF-κB inhibition or genetic silencing of IL-17RA abrogated IL-17-induced PD-L1 upregulation.
The six-gene prognostic signature and external validation suggest clinical utility. The IL-17/ IL-17 receptor alpha axis may drive immune escape by upregulating PD-L1 via NF-κB activation; therefore, it represents a potential prognostic biomarker and therapeutic target.

PMID:
42340520
Bibliographic data and abstract were imported from PubMed on 24 Jun 2026.

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