We investigated whether store-operated Ca²⁺ entry (SOCE) contributes to PD-L1 regulation in oral squamous cell carcinoma (OSCC) cells. Proteomic analysis revealed IFN-γ stimulation activates calcium-related signaling. Pharmacological SOCE inhibition with Synta66 suppressed IFN-γ-induced PD-L1 protein expression dose-dependently. Knockdown of Orai1 or STIM1 had no effect under basal conditions but significantly reduced PD-L1 induction under IFN-γ stimulation. Inhibition of CaMKII and CaMKKII also suppressed PD-L1 expression at both mRNA and protein levels. Furthermore, Orai1 or STIM1 knockdown OSCC cells exhibited reduced proliferation when co-cultured with CD8⁺ T cells, suggesting SOCE inhibition enhances immune-mediated tumor suppression.