Improved antitumor immunity of chemotherapy in OSCC treatment by Gasdermin-E mediated pyroptosis.

ABSTRACT

Oral squamous cell carcinoma (OSCC) is a malignant tumor with high mortality and poor prognosis. Many OSCC patients have low response rate to current treatments including immunotherapies largely due to the immune-suppressive tumor microenvironment (TME). Chemotherapy could induce immunogenic cell death (ICD), a type of cell death such as pyroptosis and necroptosis, which has proved to be capable to alter the immune-suppressive TME and beneficial for better anti-tumor effect. GSDME, a key protein of pyroptosis, is however often silenced in tumors due to abnormal methylation. To overcome these limitations, we utilizied methyltransferase inhibitor (decitabine, DAC) to trigger pyroptosis of tumor cells, combined with chemodrug cisplatin (DDP) and immune checkpoints inhibitors to amplify the immunotherapies outcomes. To the best of our knowledge, this is the first study of tumor suppressive effect of GSDME in OSCC. Our investigation demonstrated that stimulation of GSDME expression could improve the sensitivity of chemotherapeutics, activate inflammatory tumor cell pyroptosis and alter the tumor immune-suppressive microenvironment, providing an important perspective for clinical OSCC treatment.