An intermediate-crystalline phase manganese nanoadjuvant potently activates cGAS-STING signaling and antitumor immunity via immunometabolism normalization

Manganese (Mn 2+ ) serves as an inorganic activator of the cyclic GMP-AMP synthase- stimulator of interferon genes (cGAS-STING) pathway. However, its activation efficiency remains lower than conventional organic STING agonists, hindering widespread applications in immune modulation and therapy. Herein, we report an intermediate-crystalline phase manganese layered double hydroxide/oxide (Mn-LDH/O 150 ) nanocomposite, featuring both LDH and LDO structural phases, as a potent cGAS-STING activator. Surprisingly, Mn-LDH/O 150 induced a type-I interferon level significantly higher than pure Mn-LDH or LDO phase nanocomposites, and comparable to organic STING agonists (cGAMP/diABZI). Mechanistically, conventional Mn nanocomposite impairs energy metabolism in dendritic cells and significantly reduces mitochondrial ATP production. In contrast, Mn-LDH/O 150 modulates mitochondrial metabolism by normalizing the electron transport chain (ETC) process, which termed “immunometabolism normalization”, thereby promoting ATP production that in turn facilitates cGAMP synthesis and STING activation. In mice models, Mn-LDH/O 150 acts as a potent immune adjuvant in inducing antibodies production and T cell responses. Using a model antigen (ovalbumin) and melanoma neoantigens, we further demonstrate the excellent activity of Mn-LDH/O 150 -based vaccine in inducing antitumor immunity to prevent tumor progression and metastasis. Our discoveries highlight the crucial involvement of energy metabolism in modulating STING activation, and present a simple yet translational material engineering approach for boosting metalloimmunotherapy.