CD38 degrades MAVS through mitophagy to inhibit type I interferon secretion in nasopharyngeal carcinoma cells and impairs CD8+T cell-mediated anti-tumor immunity

Activating the type I interferon response in tumor cells and enhancing T cell-mediated anti-tumor immunity have broad clinical applications in tumor immunotherapy. However, the detailed mechanisms underlying the antitumor immune response and type I interferon response in nasopharyngeal carcinoma (NPC) remain unclear and require further elucidation. In this study, we identify CD38 in NPC cells as a key mediator impairing T cell antitumor immunity. Mechanistically, CD38 induces mitochondrial autophagy through PHB2, enhances the interaction between PHB2 and MAVS, leading to the degradation of MAVS protein, and inhibits the type I interferon response and CD8+T cell-mediated anti-tumor immunity. Importantly, CD38 promotes tumor progression and reduces the proportion of CD8+T cells and IFNγ+CD8+T cells in vivo via MAVS. In conclusion, these findings reveal previously unrecognized roles and mechanisms of CD38 in regulating anti-tumor T cell immunity, suggesting that inhibition of CD38 could initiate tumor-targeted immune responses, enhance anti-tumor immunity in patients, and provide new therapeutic strategies for NPC. Activating type I interferon (IFN-I) is beneficial for tumor therapy but how IFN-I is activated in nasopharyngeal carcinoma (NPC) remains unclear. The authors here show that targeting CD38 in NPC cells can inhibit MAVS degradation, promote IFN-I production and improve tumor prognosis via enhanced CD8 T cell response.