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

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 < 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. 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.