DNA Sensors in Immune Dysregulation: Mechanisms, Crosstalk, and Therapeutic Implications of STING-Dependent and STING-Independent Signaling Pathways

DNA sensors are core innate immune mediators that recognize pathogen-derived and endogenous DNA, driving type I interferon and inflammatory responses in anti-infectious defense, tumor immunosurveillance, and autoimmune diseases. By three rigorous definition criteria, this review systematically distinguishes bona fide direct DNA sensors from pathway regulators and cross-regulatory nucleic acid sensing hubs. It delineates the molecular mechanisms and crosstalk of STING-dependent and STING-independent sensing pathways, focusing on three core regulatory nodes: DNA-PK, TLR9–TLR7, and ADAR1–ZBP1. Non-canonical STING-independent functions of cGAS in genomic stability, autophagy, and metabolic reprogramming are also addressed. A “dose–space–time” three-dimensional framework is proposed as a working conceptual model. Finally, this review critically evaluates clinical translation bottlenecks of targeted therapies and outlines precision intervention strategies enabled by frontier technologies, providing an integrated reference for mechanistic and translational research on DNA-sensing networks.