Many cells located in the tumor microenvironment function to protect or promote the ability of tumor cells to escape immune destruction. Previous studies have shown that programmed death ligand-1 (PD-L1), a ligand of the B7 superfamily, is expressed on a series of human tumors and can inhibit anti-tumor immune responses. Interferon-γ (IFN-γ), a cytokine produced and secreted by inflammatory cells in the tumor microenvironment, is a main stimulator of PD-L1 expression in tumor cells. Making clear the mechanism of IFN-γ induced the expression of PD-L1 on tumor cells that is benefit to find a way to inhibit the function of PD-L1 and improve cancer cell-reactive immune responses. Herein, we have identified protein kinase D isoform 2 (PKD2) as an important regulator of PD-L1 expression on human oral squamous carcinoma cells induced by IFN-γ. IFN-γ induced the expression of PD-L1 and PKD2 in human oral squamous carcinoma Tca8113 in both time and dose dependent manner. The expression of PD-L1 was decreased significantly after PKD2 knockdown with shRNA/siRNA interference or PKD chemical inhibitor following induction with IFN-γ. The apoptosis of CD8(+) T cell which is induced by tumor cells via PD-1/PD-L1 pathway was significantly decreased, as a result, the anti-tumor effects of tumor antigen specific T cell were increased in vivo. Together, these data combined with our previous results, indicate PKD2 as an important target candidate for tumor biotherapy. Inhibition of PKD2 activation not only inhibits PD-L1 expression and promotes an anti-tumor effect, but also decreases drug resistance in chemotherapy.