Talazoparib engages innate immune activation via PARP trapping–dependent cGAS/STING activation in Ewing Sarcoma

: Ewing sarcoma (EwS) shows a limited clinical response to poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi), despite promising preclinical data. In this study, we compared five PARPi with different PARP-trapping capacities in PDX-derived cell lines and mouse models. Talazoparib, the strongest PARP-trapping agent, showed markedly greater efficacy than olaparib or veliparib. It triggered extensive DNA damage, micronuclei formation, and activation of the cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) pathway, leading to robust type I interferon and pro-inflammatory cytokine release, an effect not seen in osteosarcoma. In vivo, talazoparib also reshaped the tumor microenvironment, increasing macrophage infiltration and reducing tumor growth. In vitro, conditioned media from treated EwS cells promoted M0-like macrophage polarization towards an inflammatory M1-like status. These immunostimulatory effects were initiated by tumor-derived interferons and were absent in talazoparib-resistant and olaparib-treated EwS cells, underscoring the importance of the PARP trapping activity of PARPi rather than catalytic inhibition. Combination of talazoparib with exogenous 2'-3'-cyclic GMP-AMP (cGAMP) does not further increase phagocytosis of EwS cells when co-cultured with macrophages, and no additive effects were observed under the tested conditions. Thus, talazoparib is a potent cytotoxic agent with innate immune activation/macrophage-mediated effects, prompting further clinical evaluation in this tumor type.