Emerging Nanomaterials for Activation of the cGAS–STING Pathway in Cancer Immunotherapy

The cyclic guanosine monophosphate–adenosine monophosphate synthase–stimulator of interferon gene (cGAS–STING) signaling pathway has emerged as a pivotal bridge between innate and adaptive immunity, holding immense potential to reverse the immunosuppressive tumor microenvironment and convert “cold” tumors into “hot” tumors. However, the clinical translation of STING agonists is limited by their poor cytosolic delivery, rapid clearance, and potential systemic toxicity. Notably, engineered nanomaterials provide a transformative solution by allowing precise, spatiotemporal activation of this pathway. In this review, we critically examined the latest advances in nanotechnology-enabled cGAS–STING activation strategies. Beyond serving as mere delivery vehicles for agonists, we have highlighted multifunctional nanoplatforms that execute a robust immune cycle by synergizing with immunogenic cell death inducers—including chemotherapy, radiotherapy, phototherapy, and sonotherapy. Additionally, we discussed upcoming immunotherapy paradigms, such as metal-ion-mediated metallo-immunotherapy, tumor-associated macrophage repolarization, and in situ vaccination. Finally, we provide a comprehensive analysis of translational limitations—from biocompatibility to manufacturing scalability—offering promising perspectives on the design of next-generation nanomedicines to enhance clinical immunotherapy outcomes.