The role of PARP inhibitors in the cross-talk between DNA damage and activation of the cGAS/STING immune response in Ewing sarcoma cells

Inhibition of poly (ADP-ribose) polymerase (PARP)1 in cancer therapy is an adopted strategy to treat cancers where DNA repair is defective, particularly in those tumors in which mutations in BRCA1/2 genes or alterations mimicking BRCA1/2 loss occur. In Ewing sarcoma (EWS) the fusion product EWS::FLI1 impairs the correct functioning of the homologous recombination (HR) system by sequestering BRCA1, leading to a dysregulated transcription process and a consequent accumulation of R-loops. EWS sensitivity to PARP inhibitors (PARPi) has been demonstrated in several preclinical studies; yet, acquired resistance remains a major challenge that hinders the clinical success of PARPi treatment. Here, we demonstrated that PARP1 inhibition is relevant in promoting changes not only in tumor cells but also in the immune system. Indeed, PARP1 inhibition prompts double-stranded DNA (dsDNA) and micronuclei formation, triggers the cGAS/STING/IFNs pathway activation and enhances recruitment and polarization of macrophages. In addition, the PARPi-resistant model developed shows an impaired activation of the cGAS/STING/IFNs pathway which is related to a weak macrophages-mediated immune response. A further elucidation of pathways and mechanisms that contribute to or are affected by the PARPi resistance is urgently needed to improve the treatment response and provide novel therapeutic strategies for EWS patients.