cGAS-STING and PANoptosis: Interplay, Underlying Mechanisms, and Therapeutic Targets

The cGAS-STING pathway is an essential cytosolic DNA sensing mechanism that activates innate immune responses upon detection of microbial or aberrant self-DNA. This evolutionarily conserved signaling axis plays critical roles in autoimmune diseases, sterile inflammation, and cellular senescence. While its transient activation provides protective immunity, dysregulated cGAS-STING signaling contributes to the pathogenesis of various inflammatory and autoimmune conditions. Growing evidence indicates its functional convergence with multiple cell death pathways-particularly PANoptosis, a distinct inflammatory programmed cell death (PCD) pathway that integrates key features of pyroptosis, apoptosis, and necroptosis. The dynamic interplay between cGAS-STING signaling and PANoptosis has emerged as an important pathogenic mechanism across multiple diseases, revealing new therapeutic opportunities. In this review, we propose a unifying conceptual framework in which cGAS-STING activation functions as a predominant upstream driver of PANoptosis across diverse pathological contexts, orchestrated through a convergent molecular axis involving cytosolic DNA sensing, ZBP1-PANoptosome assembly, and coordinated inflammatory cell death. We begin by outlining the core molecular architecture of the cGAS-STING pathway and its implications in disease. We then examine the mechanisms and pathophysiological consequences of cGAS-STING -PANoptosis crosstalk in various disorders, followed by recent advances in therapeutic strategies specifically targeting this interface. Finally, we discuss translational challenges, such as the poor bioavailability and systemic toxicity of conventional STING agonists, and highlight innovative solutions including nanomedicine-based delivery systems that enable tumor-specific activation while minimizing off-target effects. By highlighting the therapeutic potential of pharmacological modulation at this junction, we identify promising strategies for treating inflammation-associated diseases.