IFI16 inhibits DNA repair that potentiates type-I interferon-induced antitumor effects in triple negative breast cancer

Tumor DNA-damage response (DDR) has an important role in driving type-I interferon (IFN)-mediated host antitumor immunity, but it is not clear how tumor DNA damage is interconnected with the immune response. Here, we report the role of IFN-γ-inducible protein 16 (IFI16) in DNA repair, which amplifies the stimulator of IFN genes (STING)-type-I IFN signaling, particularly in triple-negative breast cancer (TNBC). IFI16 is rapidly induced and accumulated to the histone-evicted DNA at double-stranded breakage (DSB) sites, where it inhibits recruitment of DDR factors. Subsequently, IFI16 increases the release of DNA fragments to the cytoplasm and induces STING-mediated type-I IFN production. Synergistic cytotoxic and immunomodulatory effects of doxorubicin and type-I IFNs are decreased upon IFI16 depletion in vivo. Furthermore, IFI16 expression correlates with improved clinical outcome in patients with TNBC treated with chemotherapy. Together, our findings suggest that type-I IFNs and IFI16 could offer potential therapeutic strategies for TNBC. [Display omitted] •IFI16 is rapidly recruited to histone-evicted DNA at double-strand breakage sites•IFI16 inhibits recruitment of DNA repair factors to the sites of DNA damage•IFI16 induces accumulation of cytosolic DNA and activates STING signaling•IFI16 mediates antitumor effects of doxorubicin and type-I IFNs against TNBC Ka et al. show that IFI16 inhibits DNA repair by binding to histone-evicted DNA at damaged DNA sites and thereby induces the accumulation of cytosolic DNA that promotes STING-induced type-I IFN signaling. IFI16 could be a key mediator in DNA-damage-induced antitumor immunity in triple-negative breast cancer (TNBC).