Recent breakthroughs have elucidated DNA-PKcs’s critical function in macrophage biology, where it orchestrates DNA sensing mechanisms with mTORC2/Rictor/Myc-dependent proliferative signaling, revealing a novel therapeutic avenue for overcoming PD-1/PD-L1 resistance through tumor microenvironment reprogramming [172,173]. The gene discussed is PRKDC; the disease is neoplasm.