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

  • Dig Dis Sci. 2026 Jun 24. doi: 10.1007/s10620-026-10076-8.
Xinyang Li  #  1  2  3 ,  Ya Wang  #  1  2  3 ,  Chuan Shen  1  2  3 ,  Ruolan Gu  1  2  3 ,  Mingjie Liu  1  2  3 ,  Ying Xiao  1  2  3 ,  Yuexia Liu  1  2  3 ,  Luyuan Ma  1  2  3 ,  Caiyan Zhao  4  5  6
Affiliations
  • 1. Department of Infectious Diseases, Hebei Medical University Third Hospital, Shijiazhuang, 050000, Hebei, China.
  • 2. Clinical Research Center for Infectious Disease of Hebei Province, Shijiazhuang, 050000, China.
  • 3. Hebei Key Laboratory for Diagnosis, Treatment, Emergency Prevention and Control of Critical Infectious Diseases, Shijiazhuang, 050000, China.
  • 4. Department of Infectious Diseases, Hebei Medical University Third Hospital, Shijiazhuang, 050000, Hebei, China. [email protected].
  • 5. Clinical Research Center for Infectious Disease of Hebei Province, Shijiazhuang, 050000, China. [email protected].
  • 6. Hebei Key Laboratory for Diagnosis, Treatment, Emergency Prevention and Control of Critical Infectious Diseases, Shijiazhuang, 050000, China. [email protected].
  • # Contributed equally.
PMID: 42340520 DOI: 10.1007/s10620-026-10076-8
Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusion: 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.

Keywords
Hepatocellular carcinoma; IL-17; IL-17RA; Immunity; PD-L1.
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