DDX41 facilitates PD-L1-mediated immune escape in OSCC via the phase separation and activation STING pathway.

DEAD-box helicase 41 (DDX41) functions as an oncogene in multiple cancers and is associated with immune response. However, the specific role of DDX41 in oral squamous cell carcinoma (OSCC) has not yet been elucidated. The data from public databases show that DDX41 protein expression is elevated in OSCC tumor tissues and linked to poor prognosis. Loss of DDX41 in OSCC cells leads to an inhibition in the ability of tumor proliferation and invasion. Mechanistically, DDX41 undergoes liquid-liquid phase separation with STING, forming biomolecular condensates that potentiate PD-L1 upregulation through the STING-TBK1-NF-κB pathway. And, blocking DDX41 in the OSCC mouse model confirmed that inhibition of DDX41 decreased PD-L1-mediated immune escape via the STING-TBK1-NF-kB pathway. Flow cytometry analysis revealed significantly improved tumor immune infiltration upon DDX41 knockdown, as evidenced by altered immune cell populations. Finally, clinical sample analysis revealed that DDX41 expression is associated with poor prognosis in OSCC patients and correlates with downstream proteins. Our results identify a novel mechanism by which DDX41, functioning as a cytosolic DNA sensor, promotes PD-L1-mediated tumor immune escape in OSCC via sustaining the STING-TBK1-NF-κB signaling pathway, providing both a potential therapeutic target and diagnostic indicator for this malignancy.