Orai1- and STIM1-mediated calcium signaling controls PD-L1 expression and modulates antitumor immunity in oral cancer

This study investigated the regulation of PD-L1 expression by calcium signaling in oral squamous cell carcinoma (OSCC). We found that IFN-γ stimulation markedly altered the intracellular proteome and activated calcium-associated pathways. Pharmacological inhibition of store-operated calcium entry (SOCE) using the Orai1 inhibitor Synta66 suppressed IFN-γ-induced PD-L1 expression in a dose-dependent manner. Consistently, knockdown of Orai1 or STIM1 attenuated PD-L1 induction under IFN-γ stimulation, while basal expression remained unchanged. Inhibition of CaMK2 and CaMKK2 also reduced PD-L1 expression, indicating involvement of calmodulin-dependent kinase pathways. Functionally, Orai1 or STIM1 knockdown enhanced CD8⁺ T cell–mediated suppression of OSCC cell proliferation. Collectively, these results demonstrate that SOCE-mediated calcium signaling and downstream kinases regulate IFN-γ-induced PD-L1 expression and suggest that targeting SOCE components could represent a novel therapeutic approach to overcoming tumor immune evasion in OSCC. (132 words) • IFN-γ reshapes the proteome and activates calcium pathways in oral squamous carcinoma. • SOCE and CaM-dependent kinases control IFN-γ–induced PD-L1 expression in OSCC. • Targeting SOCE boosts CD8⁺ T cell suppression of OSCC, offering strategy to block immune evasion.