Inorganic nanomaterials activate the cGAS-STING pathway for tumor treatment.

Abstract

The cGAS-STING pathway serves as a central hub for DNA-triggered innate immune activation in tumors. Nevertheless, the clinical translation of stimulator of interferon genes (STING) agonists remains hindered by challenges such as rapid in vivo degradation, inefficient cytosolic delivery, and the risk of systemic inflammation. Inorganic nanomaterials, leveraging their high specific surface area, tunable size and morphology, and unique surface chemical properties, provide an ideal platform for the precise delivery and spatiotemporally controlled release of STING agonists. Furthermore, these materials can induce the release of double-stranded DNA (dsDNA) to activate STING while also synergistically potentiating STING activation through the induction of immunogenic cell death or the release of specific metal ions. This review highlights that the application of inorganic nanomaterials in STING pathway activation extends beyond simple agonist delivery to encompass precise spatiotemporal control and modulation of signal intensity. We systematically outline design strategies for inorganic platforms that facilitate agonist protection and stimuli-responsive release. Furthermore, we discuss their synergistic integration with therapeutic modalities, including radiosensitization, reactive oxygen species (ROS) induced DNA damage, and immunogenic cell death (e.g., pyroptosis and ferroptosis), ultimately contributing to the establishment of a cGAS-STING amplification immune circuit. By achieving synergistic integration of delivery, activation, and potentiation, inorganic nanomaterials enhance both the efficacy and safety of STING-targeted immunotherapy, realizing the integrated functional advantage of "carrier-adjuvant-inducer" and offering a new paradigm for cancer immunotherapy.