cGAMP-liposome: A versatile and scalable STING agonist adjuvant for enhanced anti-infective and antitumor immunity.

The Stimulator of Interferon Genes (STING) pathway is a promising target for vaccine adjuvants and cancer immunotherapy, but the clinical application of the endogenous STING agonist 2',3'-cGAMP is hindered by poor membrane permeability, enzymatic degradation, and rapid renal clearance. To address these barriers, we developed a liposome formulation of cGAMP (cGAMP-Lipo) for intramuscular administration. The optimized cGAMP-Lipo exhibited high encapsulation efficiency (≥90 %), a uniform size of 70-80 nm, and enhanced STING activation in THP-1 cells with a 37-fold lower EC50 (45.85 nM) compared to free cGAMP. In vivo, cGAMP-Lipo significantly boosted antigen-specific immune responses, increasing anti-RBD IgG titers by up to 18-fold relative to the aluminum adjuvant and promoting Th1-skewed immunity (IgG2c/IgG1 ratio = 29.6) with a high proportion of effector CD8⁺ T cells. In a B16-OVA melanoma model, cGAMP-Lipo achieved substantial tumor growth inhibition and enhanced CD8⁺ T cell infiltration. Pharmacokinetic studies revealed that cGAMP-Lipo formed a sustained depot at the injection site, extending the local half-life from 0.50 h to 7.09 h and increasing local exposure by 43-fold. Moreover, the manufacturing process was successfully scaled up to 1 L with consistent batch-to-batch reproducibility. Collectively, this work establishes cGAMP-Lipo as a potent, durable, and scalable STING agonist adjuvant platform with strong potential for clinical translation in both infectious disease vaccination and cancer immunotherapy.