Beyond Agonist Delivery: Metallic Nanomaterials as Active Regulators of cGAS-STING Signaling in Cancer Immunotherapy

Abstract The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway represents a pivotal innate immune signaling axis that bridges cytosolic DNA sensing with type I interferon and pro-inflammatory cytokine production. However, the clinical translation of STING agonists, particularly cyclic dinucleotides (CDNs), is limited by poor membrane permeability, rapid enzymatic degradation, unfavorable pharmacokinetics, and dose-limiting systemic toxicity. Metallic nanomaterials have emerged as versatile platforms for overcoming these barriers because their coordination chemistry and tunable physicochemical properties enable the efficient loading, stabilization, and cytosolic delivery of CDNs and other STING agonists. Beyond serving as delivery vehicles, metallic nanomaterials can actively regulate cGAS-STING signaling through controlled ion release, redox reactions, catalytic generation of reactive oxygen species, and induction of nuclear or mitochondrial DNA damage. Selected metal ions, such as Mn2+ and Zn2+, may further potentiate pathway activation by modulating cGAS activity, cGAMP synthesis, STING responsiveness, or downstream signaling. This review summarizes current advances in metal-ion-mediated cGAS-STING activation and examines how metal ions and metallic nanostructures integrate agonist delivery, intrinsic pathway activation, and tumor microenvironment modulation. By linking nanoscale material design with innate immune signaling, we highlight emerging principles, translational challenges, and opportunities for developing next-generation metallic nanomaterials for cGAS-STING-based cancer immunotherapy.