PRKDC encodes DNA-dependent protein kinase catalytic subunit (DNA-PKcs), a serine/threonine kinase that functions as a molecular sensor for DNA damage. The protein is recruited to DNA double-strand breaks (DSBs) by Ku proteins and serves dual roles: it phosphorylates multiple substrates required for non-homologous end joining (NHEJ) and V(D)J recombination, and acts as a scaffold organizing repair proteins at damage sites. DNA-PKcs also contributes to ribosomal RNA processing and modulates transcription through phosphorylation of transcription factors and chr8 regulators. Beyond DNA repair, it suppresses innate immune signaling by phosphorylating cGAS and PARP1 within the cGAS-STING pathway. PRKDC dysregulation is implicated in multiple cancers. In osteosarcoma, PRKDC hyperactivation recruits GDE2 to stabilize GNAS, activating AKT and conferring doxorubicin resistance; inhibition with AZD7648 sensitizes tumors to chemotherapy 1. Conversely, DNA-PKcs inhibition with NU7441 enhances tumor immunogenicity by increasing MHC-I expression and neoantigen diversity, expanding neoantigen-reactive T cell infiltration and restoring responsiveness to immune checkpoint blockade 2. In gastric cancer, PRKDC upregulation via the hsa_circ_0136666-miR-375 axis phosphorylates PD-L1, promoting immune escape 3. Clinical deficiency of PRKDC causes atypical severe combined immunodeficiency with inflammatory granulomas and autoimmunity, highlighting its critical role in adaptive immunity 4.