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Published on: October 17, 2025

PD-L1 upregulated by IGF1R via the PI3K/AKT/NF-κB axis induces sorafenib resistance in hepatocellular carcinoma

Tao Zhu1, Chunmei Xie2, Qianqian Shao1

  • 1Medical School, Anhui University of Science & Technology, Huainan, Anhui 232001, China.

Molecular Immunology
|August 21, 2026
PubMed
Abstract

Insights

Insulin-like growth factor 1 receptor (IGF1R) drives sorafenib resistance in liver cancer by increasing programmed death-ligand 1 (PD-L1) through the PI3K/AKT/NF-κB pathway. Targeting this axis may overcome resistance to hepatocellular carcinoma (HCC) therapies.

Area of Science:

  • Hepatocellular carcinoma (HCC) research
  • Cancer signaling pathways
  • Targeted therapy resistance mechanisms

Background:

  • Aberrant insulin-like growth factor 1 receptor (IGF1R) activation is linked to hepatocellular carcinoma (HCC) treatment resistance.
  • The precise mechanism connecting IGF1R to programmed death-ligand 1 (PD-L1) and sorafenib resistance in HCC remains incompletely understood.

Purpose of the Study:

  • To elucidate the molecular pathway by which IGF1R transcriptionally upregulates PD-L1.
  • To investigate the role of the PI3K/AKT/NF-κB signaling cascade in this process.
  • To determine how this axis contributes to sorafenib resistance in HCC.

Main Methods:

  • Analysis of the IGF1R-PI3K/AKT/NF-κB-PD-L1 axis in HCC clinical samples and cell lines using immunohistochemistry and Western blotting.
  • Functional assays (CCK8, colony formation, Transwell, JC-1, Annexin V-FITC/PI) to assess cellular effects.
  • Chromatin immunoprecipitation (ChIP) and dual-luciferase reporter assays to confirm transcriptional regulation; in vivo studies in mouse xenograft models.

Main Results:

  • IGF1R overexpression in HCC correlated with increased sorafenib IC50 and activated PI3K/AKT/NF-κB signaling.
  • NF-κB directly binds the PD-L1 promoter, driving its transcription; PI3K inhibition reversed IGF1R-induced PD-L1 upregulation and restored sorafenib sensitivity.
  • In vivo, IGF1R activation promoted tumor growth and attenuated sorafenib efficacy, while PD-L1 modulation reciprocally affected tumor suppression and sorafenib response.

Conclusions:

  • IGF1R upregulates PD-L1 via the PI3K/AKT/NF-κB pathway through direct NF-κB-mediated transcriptional activation.
  • PD-L1 acts as a critical downstream effector, mediating sorafenib resistance in HCC.
  • This pathway represents a potential therapeutic target for overcoming sorafenib resistance in HCC.
Keywords:
Drug sensitivityHepatocellular carcinomaIGF1RPD-L1PI3K/AKT/NF-κB signaling

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