Manganese in metalloimmunotherapy: From molecular targets to material engineering and translational therapeutics

Immunotherapies play a crucial role in maintaining human health by modulating the immune system through the use of immune cells, antibodies, and vaccines. Among emerging therapeutic modalities, metal-based immunotherapy has shown promise by utilizing the immune-modulating properties of metals, metal ions, and metallic compounds for disease intervention. Specifically, Mn^{2 +} has been demonstrated to potently activate the cGAS/STING signaling axis, a key pathway in innate immune activation for immunotherapeutic strategies. Notwithstanding these advantages, the clinical translation of free Mn²⁺ is substantially hindered by three critical limitations: rapid in vivo degradation, poor transmembrane permeability as a hydrophilic cation, and potential cytotoxicity. To address these bottlenecks, advanced controlled-release technologies have been developed to enable spatiotemporal regulation of Mn²⁺ in biological systems, thus improving therapeutic efficacy and reducing off-target effects. In this review, we delve into the intricate molecular mechanisms by which manganese ions regulate immune responses and explores the cutting-edge technologies employed in the fabrication of manganese-based materials. Then, we discussed the latest research on the use of manganese-based materials in antiviral, antibacterial and anticancer applications. Through its comprehensive comparative analysis, this review seeks to inspire next-generation research in manganese-based immunotherapy, unmasking its transformative potential across interdisciplinary frontiers and thereby catalyzing paradigm shifts in translational medicine.