Zinc-based nanoplatforms for cancer immunotherapy achieved through the cyclic GMP-AMP synthase-stimulator of interferon genes pathway: Bridging tumor metabolism and immune activation.

Abstract

Cancer immunotherapy has substantially advanced cancer treatment; however, durable responses remain uncommon in tumors with low immunogenicity and strongly suppressive tumor microenvironments (TME). Among innate immune pathways, cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) signaling has attracted considerable attention because of its ability to initiate broad antitumor immune responses. Despite this promise, the therapeutic use of STING agonists is limited by rapid systemic clearance, insufficient tumor accumulation, and dose-limiting inflammatory toxicity. Simultaneously, metabolic adaptations within tumors, including elevated glycolytic flux, lactate enrichment, and redox imbalance, continue to undermine immune cell function and restrict treatment efficacy. Zn-based nanoplatforms have recently emerged as versatile systems capable of simultaneously addressing both challenges. Controlled intracellular release of Zn2+ can potentiate cGAS activity and strengthen downstream STING signaling, whereas oxidative stress induced by these nanomaterials promotes DNA damage, cytosolic DNA leakage, and immunogenic cell death. These effects are not limited to the activation of innate immunity. Several Zn-containing nanoplatforms reshape the metabolic landscape of the TME by lowering lactate accumulation and partially restoring immune cell activity. Consequently, dendritic cell (DC) maturation and antigen presentation are enhanced, leading to more effective T cell-driven antitumor responses. This review examines the emerging role of Zn2+ in regulating the immune and metabolic pathways relevant to cancer therapy. We discuss current strategies for designing Zn-based nanoplatforms, with particular emphasis on the mechanisms linking metabolic intervention to cGAS-STING activation. Dedicated sections examine Zn-based platforms for drug delivery and photodynamic and sonodynamic therapies, as well as their capacity to promote DC activation and combination immunotherapy. Finally, we consider the major barriers to clinical translation, including biosafety, delivery efficiency, and large-scale manufacturing, and outline the directions for the development of next-generation Zn-based immunotherapeutic systems. STATEMENT OF SIGNIFICANCE: This review provides a comprehensive, mechanistically integrated perspective on Zn-based nanoplatforms as multifunctional immunotherapeutic systems that bridge tumor metabolic reprogramming and cGAS-STING-mediated innate and adaptive immune activation. Unlike previous reviews that primarily focused on STING agonists or Zn-based nanomaterials independently, this study highlights how tumor-responsive Zn²⁺ release, oxidative stress, DNA damage, and metabolic remodeling collectively enhance antitumor immunity. This review critically compares the design principles, therapeutic mechanisms, and translational potential of diverse Zn-based nanoplatforms and discusses the key challenges in biosafety, manufacturing, and clinical translation. This review offers a conceptual framework to guide the rational development of next-generation Zn-based nanomedicines for precision cancer immunotherapy.