PARP7 negatively regulates the type I interferon response in cancer cells and its inhibition triggers antitumor immunity

Cancer Cell. 2021 Sep 13;39(9):1214-1226.e10. doi: 10.1016/j.ccell.2021.06.018. Epub 2021 Jul 22.


PARP7 is a monoPARP that catalyzes the transfer of single units of ADP-ribose onto substrates to change their function. Here, we identify PARP7 as a negative regulator of nucleic acid sensing in tumor cells. Inhibition of PARP7 restores type I interferon (IFN) signaling responses to nucleic acids in tumor models. Restored signaling can directly inhibit cell proliferation and activate the immune system, both of which contribute to tumor regression. Oral dosing of the PARP7 small-molecule inhibitor, RBN-2397, results in complete tumor regression in a lung cancer xenograft and induces tumor-specific adaptive immune memory in an immunocompetent mouse cancer model, dependent on inducing type I IFN signaling in tumor cells. PARP7 is a therapeutic target whose inhibition induces both cancer cell-autonomous and immune stimulatory effects via enhanced IFN signaling. These data support the targeting of a monoPARP in cancer and introduce a potent and selective PARP7 inhibitor to enter clinical development.

Keywords: DNA sensing; PARP7; RBN-2397; cancer drug discovery; innate immunity; nucleic acid sensing; small-molecule inhibitor; type I interferon.

MeSH terms

  • Adaptive Immunity / drug effects
  • Animals
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Drug Resistance, Neoplasm / drug effects*
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Interferon Type I / metabolism*
  • Mice
  • Neoplasms / drug therapy*
  • Neoplasms / genetics
  • Neoplasms / metabolism
  • Nucleoside Transport Proteins / genetics*
  • Nucleoside Transport Proteins / metabolism*
  • Signal Transduction / drug effects
  • Small Molecule Libraries / administration & dosage*
  • Small Molecule Libraries / pharmacology
  • Tumor Escape / drug effects
  • Xenograft Model Antitumor Assays


  • Interferon Type I
  • Nucleoside Transport Proteins
  • Small Molecule Libraries
  • TiPARP protein, human