From genome guardian to immune modulator: the dual faces of DNA-PKcs.

Abstract

The DNA-dependent protein kinase catalytic subunit (DNA-PKcs) has long been recognized as a genome guardian, serving as a master regulator of non-homologous end joining (NHEJ), safeguarding genomic integrity and enabling adaptive immunity through V(D)J recombination. Beyond this nuclear function, DNA-PKcs is now increasingly appreciated as a context-dependent immune modulator, acting at the interface between the DNA damage response and inflammatory signaling. This review synthesizes recent advances that redefine DNA-PKcs as a versatile "molecular integrator." We delineate its structural dynamics and multifaceted regulation, and dissect its dual function in the cytoplasm, where it can either potentiate or suppress the cyclic GMP-AMP synthase and stimulator of interferon genes (cGAS-STING) pathway and even initiate STING-independent interferon responses. We further explore how dysregulation of DNA-PKcs underpins a spectrum of pathologies, from immunodeficiency and autoimmunity to cancer and neurodegeneration. Finally, we discuss the translational promise of DNA-PKcs inhibitors, which not only act as classical chemo- and radio-sensitizers but also remodel the tumor microenvironment by activating antitumor immunity. Decoding the context-dependent logic behind these dual faces is therefore paramount for developing novel therapeutics that leverage DNA-PKcs across oncology, autoimmunity, and neurodegeneration.

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