Context-Dependent cGAS-STING Activation Shapes Metastatic Progression and Dormancy

Abstract

Highlights What are the main findings? cGAS-STING signaling has context-dependent roles in metastasis. Dormant disseminated tumor cells repress STING signaling and related immune ligands in perivascular niches, enabling immune evasion and long-term persistence. What are the implications of the main findings? Temporal, cell-type, and spatial control of STING activation are critical for STING-targeted therapies and biomarker development. Rational combination strategies are needed to harness acute STING-mediated immunity while avoiding chronic, tumor-promoting inflammation. Abstract Cancer cells survive, proliferate, and metastasize in part because the immune system fails to detect and eliminate them. Moreover, the tumor microenvironment (TME) that surrounds the tumor supports cancer cell survival and resistance to chemo- and immunotherapies by inhibiting antitumor immune responses and thereby reducing the efficacy of immunotherapeutic interventions. cGAS-STING signaling senses cytoplasmic DNA and coordinates innate immune responses that shape tumor-intrinsic outcomes and the TME. Emerging evidence reveals a context-dependent, dualistic role for cGAS-STING in metastatic progression and cancer dormancy. Acute, robust activation in antigen-presenting cells promotes type I interferon responses, leading to suppression of tumor growth. By contrast, chronic, low-level cancer-intrinsic STING signaling can engage inflammatory programs that foster immune suppression and therapy resistance. Dormant disseminated tumor cells exploit niche cues to downregulate STING signaling and evade immune detection, whereas reactivation of dormant cells often involves restoration of STING activity that can promote immune elimination. In this article, we review mechanisms linking genome instability and cytoplasmic DNA to STING activation, summarize evidence for tumor-suppressive versus tumor-promoting functions across metastatic niches, and discuss how STING agonists and combination strategies may be optimized to maximize antitumor immunity while avoiding protumorigenic effects.