Tumor cells suppress radiation-induced immunity by hijacking caspase 9 signaling

Nat Immunol. 2020 May;21(5):546-554. doi: 10.1038/s41590-020-0641-5. Epub 2020 Mar 30.


High-dose radiation activates caspases in tumor cells to produce abundant DNA fragments for DNA sensing in antigen-presenting cells, but the intrinsic DNA sensing in tumor cells after radiation is rather limited. Here we demonstrate that irradiated tumor cells hijack caspase 9 signaling to suppress intrinsic DNA sensing. Instead of apoptotic genomic DNA, tumor-derived mitochondrial DNA triggers intrinsic DNA sensing. Specifically, loss of mitochondrial DNA sensing in Casp9-/- tumors abolishes the enhanced therapeutic effect of radiation. We demonstrated that combining emricasan, a pan-caspase inhibitor, with radiation generates synergistic therapeutic effects. Moreover, loss of CASP9 signaling in tumor cells led to adaptive resistance by upregulating programmed death-ligand 1 (PD-L1) and resulted in tumor relapse. Additional anti-PD-L1 blockade can further overcome this acquired immune resistance. Therefore, combining radiation with a caspase inhibitor and anti-PD-L1 can effectively control tumors by sequentially blocking both intrinsic and extrinsic inhibitory signaling.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Antineoplastic Agents, Immunological / therapeutic use*
  • B7-H1 Antigen / genetics
  • B7-H1 Antigen / metabolism
  • Caspase 9 / genetics
  • Caspase 9 / metabolism*
  • Caspase Inhibitors / therapeutic use*
  • Cell Line, Tumor
  • Chemoradiotherapy / methods*
  • Colorectal Neoplasms / therapy*
  • Disease Models, Animal
  • Drug Resistance, Neoplasm / genetics
  • Female
  • Humans
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neoplasm Transplantation
  • Pentanoic Acids / therapeutic use*
  • Signal Transduction
  • Up-Regulation


  • 3-(2-(2-tert-butylphenylaminooxalyl)aminopropionylamino)-4-oxo-5-(2,3,5,6-tetrafluorophenoxy)pentanoic acid
  • Antineoplastic Agents, Immunological
  • B7-H1 Antigen
  • Caspase Inhibitors
  • Pentanoic Acids
  • Caspase 9