Tao Zhu,1,* Niandie Cao,1,* Li Tu,1,* Shiqi Ouyang,1,* Zengli Wang,1,* Yong Liang,2 Shuping Zhou,3 Xiaolong Tang1,3 

1Medical School, Anhui University of Science and Technology, Huainan, People’s Republic of China; 2Central and Clinical Laboratory, Affiliated Huaian Hospital of Xuzhou Medical University, Huaian, People’s Republic of China; 3Department of Hepatology, First Affiliated Hospital, Anhui University of Science and Technology, Huainan, People’s Republic of China

*These authors contributed equally to this work

Correspondence: Yong Liang, Email yongl@xzhmu.edu.cn Xiaolong Tang, Email xltang2006@aust.edu.cn

Background: 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.
Methods: 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).
Results: 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 < 0.001). Crucially, genetic knockdown of either PD-L1 or ITGB4 effectively reversed this chemoresistance phenotype. In translational validation, combined pharmacological inhibition of the PD-L1/ITGB4 axis with sorafenib synergistically suppressed tumor progression in vivo, achieving > 60% greater volume reduction compared to monotherapies.
Conclusion: 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.

Keywords: programmed cell death ligand-1, integrin beta 4, resistance, FAK/AKT/mTOR, hepatocellular carcinoma