STING agonists in tumor therapy: structural pharmacology, determinants of productive activation, and barrier-matched therapeutic strategies.
The cyclic GMP-AMP synthase-stimulator of interferon genes pathway is a central innate immune axis that connects cytosolic DNA sensing with type I interferon production, dendritic-cell activation, and downstream T-cell priming. These functions have positioned stimulator of interferon genes (STING) as an attractive therapeutic target in cancer, driving the development of cyclic dinucleotides, non-nucleotide small molecules, and formulation-enabled agonist platforms. Yet early clinical experience has revealed a recurring gap between measurable target engagement and durable antitumor benefit. Understanding this gap requires a pharmacological analysis that moves beyond pathway-level description and considers agonist chemistry, binding mode, intracellular trafficking, and exposure pattern together with the tumor-context determinants that control productive immune conversion. In this review, we summarize the structural, molecular, and biochemical basis of STING agonism, with emphasis on ligand recognition, species-selective determinants, trafficking requirements, and the pharmacological consequences of route of administration and formulation design. We then use a barrier-oriented perspective to examine four recurrent limitations on productive STING agonism in tumors: compartment mismatch, metabolic constraints, extracellular cyclic GMP-AMP (cGAMP) neutralization, and chronic output drift. These barriers help explain why pathway engagement may not consistently produce antigen-presenting cell (APC)-centered interferon output, T-cell priming, and durable antitumor immunity. We close by mapping therapeutic strategies to the barrier each strategy is most likely to overcome and by outlining biomarker-guided principles for designing STING activation that is therapeutically productive, rather than merely detectable.