Unleashing Viral Mimicry: A Combinatorial Strategy to Enhance the Efficacy of PARP7 Inhibitors

Cancer cells exploit mechanisms to evade immune detection triggered by aberrant self-nucleic acids (NA). PARP7, a key player in this immune evasion strategy, has emerged as a potential target for cancer therapy. PARP7 inhibitors reactivate NA sensing, resulting in type I interferon (IFN) signaling, programmed cell death, anti-tumor immunity, and tumor regression. Cancer cells with elevated IFN-stimulated gene (ISG) scores, representing a viral mimicry-primed state, are particularly sensitive to PARP7 inhibition. This review focuses on the endogenous sources of NA in cancer and the potential to exploit elevated aberrant self-NA in cancer therapy. We describe strategies to increase cytoplamic NA levels, including targeting epigenetic control, DNA damage response, and mitochondrial function. We also discuss targeting RNA processing pathways, such as splicing and RNA editing, to enhance the immunostimulatory potential of existing NA. Combining PARP7 inhibitors with NA elevating strategies may improve cancer immunotherapy, especially for tumors with high ISG scores.