The tumor suppressor kinase DAPK3 drives tumor-intrinsic immunity through the STING-IFN-β pathway

Nat Immunol. 2021 Apr;22(4):485-496. doi: 10.1038/s41590-021-00896-3. Epub 2021 Mar 25.


Evasion of host immunity is a hallmark of cancer; however, mechanisms linking oncogenic mutations and immune escape are incompletely understood. Through loss-of-function screening of 1,001 tumor suppressor genes, we identified death-associated protein kinase 3 (DAPK3) as a previously unrecognized driver of anti-tumor immunity through the stimulator of interferon genes (STING) pathway of cytosolic DNA sensing. Loss of DAPK3 expression or kinase activity impaired STING activation and interferon (IFN)-β-stimulated gene induction. DAPK3 deficiency in IFN-β-producing tumors drove rapid growth and reduced infiltration of CD103+CD8α+ dendritic cells and cytotoxic lymphocytes, attenuating the response to cancer chemo-immunotherapy. Mechanistically, DAPK3 coordinated post-translational modification of STING. In unstimulated cells, DAPK3 inhibited STING K48-linked poly-ubiquitination and proteasome-mediated degradation. After cGAMP stimulation, DAPK3 was required for STING K63-linked poly-ubiquitination and STING-TANK-binding kinase 1 interaction. Comprehensive phospho-proteomics uncovered a DAPK3-specific phospho-site on the E3 ligase LMO7, critical for LMO7-STING interaction and STING K63-linked poly-ubiquitination. Thus, DAPK3 is an essential kinase for STING activation that drives tumor-intrinsic innate immunity and tumor immune surveillance.

Publication types

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

MeSH terms

  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology
  • Cell Line, Tumor
  • Death-Associated Protein Kinases / genetics
  • Death-Associated Protein Kinases / metabolism*
  • Female
  • Gene Expression Regulation, Neoplastic
  • Human Umbilical Vein Endothelial Cells / enzymology*
  • Human Umbilical Vein Endothelial Cells / metabolism
  • Humans
  • Immune Checkpoint Inhibitors / pharmacology
  • Immunity, Innate* / drug effects
  • Interferon-beta / genetics
  • Interferon-beta / metabolism*
  • LIM Domain Proteins / genetics
  • LIM Domain Proteins / metabolism
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neoplasms / drug therapy
  • Neoplasms / enzymology*
  • Neoplasms / genetics
  • Neoplasms / immunology
  • Phosphorylation
  • Signal Transduction
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Tumor Escape* / drug effects
  • Ubiquitination


  • Immune Checkpoint Inhibitors
  • LIM Domain Proteins
  • LMO7 protein, human
  • Lmo7 protein, mouse
  • Membrane Proteins
  • STING1 protein, human
  • Sting1 protein, mouse
  • Transcription Factors
  • Interferon-beta
  • DAPK3 protein, human
  • Dapk3 protein, mouse
  • Death-Associated Protein Kinases