Targeting HDAC and PARP Enhances STING‐Dependent Antitumor Immunity in STING‐Deficient Tumor

Abstract The stimulator of interferon genes (STING)‐mediated innate immune pathway plays an important role in tumor immunosurveillance. STING deficiency in tumors impairs the interferon response; however, the underlying mechanism remains unclear. Here, it is demonstrated that histone deacetylase (HDAC) suppresses STING expression by reducing H3K9 acetylation at the STING promoter. The combined inhibition of HDAC and poly(ADP‐ribose) polymerase (PARP) induced STING re‐expression and promoted cytosolic DNA accumulation, which further activated the interferon response in STING‐deficient tumors. A bifunctional HDAC and PARP inhibitor displayed potent antitumor immunity by reinducing and activating the STING pathway. Mechanistically, the bifunctional HDAC and PARP inhibitor induced “BRCAness,” thereby restoring synthetic lethality, reactivating STING expression, and promoting the infiltration and activation of T cells and dendritic cells in the tumor microenvironment. Notably, STING depletion reversed the antitumor effect. Moreover, dual inhibition of HDAC and PARP significantly enhanced the antitumor immune response to immune checkpoint blockade by inducing adaptive immune memory. These findings underscore dual HDAC and PARP inhibition as a promising therapeutic strategy for overcoming the STING pathway deficiency and augmenting antitumor immunity in cancer.