Neuroinflammation following secondary injury in spinal cord injury (SCI) constitutes a major obstacle to functional recovery. Endogenous danger signals, particularly mitochondrial DNA (mtDNA) released post-injury, can activate the cGAS-STING pathway, thereby modulating the activation state of microglia and macrophages toward a pro-inflammatory phenotype. This process unfolds within a highly interconnected network involving Toll-like receptor (TLR) signaling, reactive oxygen species (ROS), NLRP3 inflammasome assembly, and cytokine cascades. Through crosstalk with the NLRP3 inflammasome, the cGAS-STING pathway can enhance cellular susceptibility to pyroptosis. The ultimate execution of pyroptotic cell death remains contingent upon additional downstream events, including the activation of Caspase-1 and the cleavage of Gasdermin D. The state of microglia and macrophages is dynamically regulated by a convergence of multiple signaling pathways. Furthermore, the cGAS-STING pathway engages in complex bidirectional interactions with autophagy, underscoring its multifaceted regulatory functions. This review explores emerging intervention strategies targeting this pathway, including small-molecule inhibitors/agonists, genetic interventions, and smart nanomaterials, aimed at achieving precise immunomodulation within the neuroimmune microenvironment. However, the clinical translation of this field still faces significant challenges, primarily concerning issues of spatiotemporal-specific modulation, drug delivery efficiency, and interspecies differences. Future research should focus on elucidating these intricate mechanisms and developing advanced drug delivery systems to facilitate the translation of this therapeutic target from a conceptual framework into clinically effective treatment modalities.
