What type of study is this?

This is a Observational study (also classified as: Animal Study).

September 10, 2025Open Access

PD-L1/ITGB4 Axis Modulates Sensitivity of Hepatocellular Carcinoma to Sorafenib via FAK/AKT/mTOR Signaling Pathway

ZTZhu TaoAnhui University of Science and Technology NCNiandie CaoAnhui University of Science and Technology LTLi TuAnhui University of Science and Technology

Key Points

Targeting the PD-L1/ITGB4 axis significantly enhances sensitivity to sorafenib in hepatocellular carcinoma models.
High levels of PD-L1 and ITGB4 correlate with increased sorafenib resistance, as measured by reduced drug efficacy.
Functional experiments revealed that disrupting PD-L1 or ITGB4 reverses resistance to sorafenib in HCC cells.
Combined inhibition of PD-L1 and ITGB4 markedly improves sorafenib effectiveness, offering a novel treatment approach.

Abstract

Hepatocellular carcinoma (HCC) frequently develops resistance to sorafenib, a first-line treatment for advanced HCC. While PD-L1 contributes to immune evasion and direct tumor survival, its role in modulating sorafenib resistance via non-immunological pathways remains unclear. This study investigates the PD-L1/ITGB4 axis in regulating sorafenib sensitivity. Bioinformatics analysis of HCC datasets identified PD-L1/ITGB4 co-expression. Protein interaction was validated via co-immunoprecipitation (Co-IP). Functional impacts on FAK/AKT/mTOR signaling were assessed using kinase inhibitors and gene knockdown in HCC cell lines. Sorafenib sensitivity was evaluated in vitro and in xenograft models with mono- and combination therapies (PD-L1/ITGB4 inhibition ± sorafenib). PD-L1 directly interacts with ITGB4 to activate the FAK/AKT/mTOR signaling pathway, independent of its immune-regulatory functions. This interaction critically mediates sorafenib resistance in HCC, as evidenced by significantly reduced drug sensitivity in PD-L1high/ITGB4high cells (p 60% greater volume reduction compared to monotherapies. The PD-L1/ITGB4 axis drives sorafenib resistance via FAK/AKT/mTOR hyperactivation. Dual targeting of PD-L1/ITGB4 enhances sorafenib efficacy, revealing a tumor-intrinsic mechanism and proposing a novel combinatorial strategy for HCC.

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