cGAS–STING activation correlates with improved survival and enhanced checkpoint blockade response in cancerActivating a cancer-fighting immune pathway can help tumors shrink but too much may backfire

Despite major advances in T cell-directed cancer immunotherapy, many patients fail to achieve durable responses, underscoring the need for approaches that mobilize additional arms of the immune system. The cyclic GMP-AMP synthase–stimulator of interferon genes (cGAS–STING) pathway has emerged as a central cytosolic DNA sensor that initiates robust type I interferon signaling and bridges innate and adaptive antitumor immunity. Clinically, heightened cGAS–STING activity correlates with improved survival and enhanced responsiveness to immune checkpoint blockade in subset of tumor types. Preclinical studies have further demonstrated that the pharmacologic or genetic activation of cGAS–STING suppresses tumor growth, promotes dendritic cell maturation, increases effector immune infiltration, and synergizes with PD-1/PD-L1 inhibition. However, the spectrum of tumors that derive the greatest therapeutic benefit from STING activation and the mechanisms underlying pathway silencing or non-responsiveness remain incompletely defined. In this review, we integrate mechanistic, preclinical, and clinical evidence across solid tumors and hematologic malignancies to delineate the roles of cGAS–STING as both a prognostic biomarker and a therapeutic target. Our synthesis highlights the context-dependent nature of cGAS–STING signaling, with therapeutic outcomes shaped by STING pathway integrity, tumor mutational burden, cytosolic DNA load, and the immunologic composition of the tumor microenvironment. Importantly, we examine emerging evidence that excessive, systemic, or chronic STING activation can drive immune exhaustion, tolerogenic myeloid reprogramming, and treatment-limiting toxicity, which are factors likely to contribute to efficacy limitations of the first-generation STING agonists. We further discuss how rational combination strategies, optimized delivery platforms, and the kinetic control of STING activation may overcome these barriers. Collectively, this synthesis provides a conceptual framework to guide the development of next-generation immunotherapies that leverage cGAS–STING signaling while avoiding the immunosuppressive consequences of dysregulated innate immune activation.