PARP7 inhibition and a STING agonist potentiate radiation-induced immunogenicity in glioblastoma.

Glioblastoma (GBM) is the most lethal form of brain cancer with an immunosuppressive tumor microenvironment (TME). Radio- and chemotherapy can modify the TME and elicit anti-tumor immunity through the STING and type I interferon (IFN-I) pathways. STING agonists or DNA damage response inhibitors can potentiate the effects of radiation by targeting the IFN-I pathway. Here, we examined the immunogenic response of GBM cells to hypofractionated or single-dose radiation combined with a STING agonist or inhibitors targeting immune signaling (PARP7), the DNA damage response, cell cycle checkpoints or autophagy. We found that hypofractionated radiation elicited a ferroptosis-dependent IFN-I response and that the PARP7 inhibitor KMR-206 and the STING agonist diABZI enhanced the effects of radiation by activating immune cells. In patient-derived GBM cancer stem cells with low STING levels, the PARP7 inhibitor was more effective at inducing immunogenic signaling compared to the STING agonist. Our results highlight the potential of PARP7 inhibitors as a new treatment to boost anti-tumor immunity in GBM, which may be more advantageous compared to STING agonists given that STING is often downregulated in GBM.