NAD+ Metabolism-Mediated SURF4-STING Axis Enhances T-Cell Anti-Tumor Effects in the Ovarian Cancer Microenvironment

Abstract

The anti-tumor function of T cells in the ovarian cancer (OC) microenvironment influences the prognosis of OC. Previous studies have indicated that metabolic competition among microenvironmental cells regulates the function of immune cells. Recent research has shown that NAD⁺ metabolism plays a significant role in modulating immune cell activity, and increasing NAD⁺ levels is a promising therapeutic strategy to enhance the effector functions of immune cells. However, the regulatory mechanisms of NAD⁺ metabolism on the anti-tumor function of T cells in the OC microenvironment remain unclear. This study found that exogenous supplementation of NAM to increase NAD⁺ levels in T cells significantly activates the endogenous p-STING axis and downstream interferon signaling within T cells, thereby enhancing T cell activation and anti-tumor effects. Concurrently, we discovered that elevated NAD⁺ levels promote the retention of STING on the Golgi apparatus. Mechanistically, we elucidated that the increase in NAD⁺ levels mediated by NAM downregulates the expression of SURF4 protein through ubiquitination and degradation, subsequently activating the p-STING axis in T cells. Furthermore, exogenous NAM supplementation can further enhance the activation of the T cell STING axis by PARP inhibitor (PARPi)-treated OC cells, and the combination of PARPi and NAM significantly augments the anti-tumor function of T cells, inhibiting the progression of OC. Our findings provide a molecular basis for the regulation of T cell anti-tumor function by NAD⁺, highlighting the potential strategy of targeting T cell metabolic reprogramming for the treatment of OC.