Engineering Nanoimmune Interfaces for Precision STING Activation: From Molecular Engineering to Cancer Immunotherapy

Abstract The cyclic GMP-AMP synthase-stimulator of interferon gene (cGAS-STING) pathway links cytosolic DNA sensing to innate and adaptive antitumor immunity and has emerged as an attractive target for cancer immunotherapy. Despite compelling preclinical activity, the clinical translation of STING agonists remains limited by unfavorable pharmacokinetics, insufficient tumor retention, inefficient cellular uptake and cytosolic delivery, endosomal trafficking barriers, dose-limiting systemic inflammation, and context-dependent responses among tumor, stromal, and immune cell populations. In this review, we examine how nanoengineering can address these barriers by controlling the biodistribution, cellular targeting, intracellular fate, and activation kinetics of STING therapeutics. We distinguish the direct delivery of STING agonists from strategies that amplify endogenous cGAS-STING signaling by preserving cytosolic DNA or extracellular cGAMP as well as indirect activation through therapy-induced DNA damage, reactive oxygen species generation, and mitochondrial stress. We compare lipid-, polymeric-, metal-based-, biomimetic-, and tumor microenvironment-responsive platforms, with particular attention to tumor cells, dendritic cells, macrophages, downstream NK cell activation, and the vascular–immune interface. We further discuss endosomal escape, cell-selective and spatiotemporally controlled activation, combination therapy, adaptive immune resistance, clinical translation, and emerging AI-guided design approaches. Collectively, this review proposes that the therapeutic success of STING nanomedicine will depend not simply on agonist potency but on rational engineering of the nanoimmune interface to control where, when, and in which cells STING signaling is activated.