Oraov1 Potentiates Tumor Immune Evasion Via Autophagic Degradation Of Sting

Head and neck squamous cell carcinoma (HNSCC), as one of the most prevalent cancers, poses a heavy disease burden globally. Immune checkpoint inhibitors (ICIs) is a promising option for managing cancers, however, the efficacy of which for HNSCC is only 15-20%. ORAOV1 is a driver oncogene implicating in HNSCC progression. our preliminary data showed that ORAOV1-high tumors possess worse immunotherapeutic response and is negatively related to STING; it remains uncharacterized that whether ORAOV1 contributes to STING degradation and accounts for the immune escape of HNSCC. Thus, our study seeks to illuminate the function and mechanism of ORAOV1 in attenuating the IFN-I signaling. Clinical specimens were first utilized to analyze the relationship between ORAOV1 and STING as well as anti-tumor immunity; in vitro, immunoprecipitation, mass spectrometry, and immunofluorescence were utilized to elucidate the detailed mechanism; in vivo tumor models of HNSCC were constructed to explore the potential of targeting autophagy in boosting immunotherapeutic efficacy. The in vitro studies revealed that ORAOV1 could bind to the first tryptophan-aspartic acid (WD) repeat sequence of RACK1, subsequently recruiting the ATG5-ATG12 complex and initiating autophagic degradation of STING. Preclinical studies indicated that combined use of autophagy inhibitors can boost the effectiveness of αPD-1 therapy in ORAOV1-high HNSCC tumors by potentiating anti-tumor immunity. ORAOV1 inhibits anti-tumor immunity and mediates tumor immunotherapy resistance by binding to RACK1 and initiating autophagy for degrading STING, thus blocking IFN-I activation