Antimicrobial peptide Pt5-1c exerts potent immunomodulatory and antiviral effects by facilitating cellular delivery of cGAMP.

The cGAS-STING signaling axis constitutes a pivotal defense mechanism in innate immunity, where the second messenger cyclic 2', 3'-GMP-AMP (hereafter referred to as cGAMP) orchestrates the induction of type I interferons (IFNs) to combat viral infections. Despite its therapeutic potential, the clinical translation of cGAMP is severely hampered by its intrinsic physicochemical properties-high hydrophilicity and polyanionic charge-which result in poor membrane permeability and suboptimal bioavailability. Here, we identify Pt5-1c, a zebrafish phosvitin-derived antimicrobial peptide, as a potent immunomodulatory agent that overcomes this delivery bottleneck. Our results demonstrate that Pt5-1c significantly amplifies cGAMP-mediated immune signaling by enhancing its extracellular availability. Mechanistically, Microscale Thermophoresis (MST) and LC-MS/MS analyses reveal that Pt5-1c directly complexes with cGAMP, facilitating its efficient delivery to target cells, thereby triggering a robust STING-dependent cascade and downstream effector expression. In both in vitro and in vivo models, the Pt5-1c/cGAMP synergy elicited a superior interferon response and conferred profound protection against virus challenges. This study not only uncovers a novel functional role for antimicrobial peptides as facilitators of intracellular signaling but also provides a strategic framework for the development of next-generation STING-targeted antiviral immunotherapies.