Nanoengineered STING agonists for cancer therapy: toward immunodynamic control.

Abstract

Activation of the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway is a mechanistically compelling strategy for cancer immunotherapy, but first-generation STING agonists have shown limited clinical activity despite clear pharmacodynamic induction of interferon-related signals. This translational gap suggests that therapeutic benefit depends not only on pathway engagement but also on where, in which cells, at what amplitude, and for how long STING is activated. In this review, we summarize the cellular context of cGAS-STING signaling, the pharmacological evolution and clinical experience of STING agonists, and the major barriers imposed by route, species differences, biological heterogeneity, and systemic inflammatory toxicity. We then examine how nanoengineering may improve agonist protection, cytosolic access, tissue and cell-type selectivity, and temporal exposure. Importantly, we distinguish improved delivery or tumor accumulation from direct evidence of altered signaling kinetics or a wider therapeutic window. Representative lipid, polymeric, inorganic, biogenic, biomimetic, antibody-directed, and prodrug-based platforms are evaluated together with mechanism-based combination sequencing, hematologic malignancy-specific considerations, biomarker-guided patient selection, repeated-dose safety, and manufacturability. Overall, nano-STING therapy should be developed toward immunodynamic control rather than simple delivery enhancement, with benefit judged by the relationship among delivery, cell-resolved pharmacodynamics, antitumor efficacy, and toxicity.