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

Abstract

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 DAPK3 as a previously unrecognized driver of anti-tumor immunity through the STING pathway of cytosolic DNA sensing. Loss of DAPK3 expression or kinase activity impaired STING activation and interferon-β (IFN-β)-stimulated gene induction. DAPK3 deficiency in IFN-β-producing tumors drove rapid growth and reduced infiltration of CD103 ⁺CD8α ⁺DCs and cytotoxic lymphocytes, attenuating response to cancer chemo-immunotherapy. Mechanistically, DAPK3 coordinated post-translational modifications 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-TBK1 interaction. Comprehensive phospho-proteomics uncovered a DAPK3-specific phosphosite 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.