β-Arrestin-Mediated Activation of Chemokine Receptor CCR7 by Human β-Defensin-3 Drives Oral Squamous Cell Carcinoma Progression

Human β-defensin-3 (hBD3), an epithelial-derived antimicrobial peptide, was recently identified as a regulator of oral squamous cell carcinoma (OSCC) progression through its interaction with the chemokine receptor CCR7a key mediator of immune cell trafficking and tumor metastasis. In this study, we aimed to clarify the structural and mechanistic basis of hBD3-induced CCR7 activation by employing molecular docking combined with atomic-level molecular dynamics simulations. Binding of hBD3 induced marked conformational rearrangements in CCR7, enhancing β-arrestin-2 recruitment and initiating noncanonical intracellular signaling cascades. Comparative studies with the endogenous CCR7 ligands CCL19 and CCL21 revealed that hBD3 exhibited dual functionality: intact disulfide bonds confer agonistic properties by promoting receptor activation, whereas the disruption of these bonds converts the peptide into an antagonist. Moreover, distinct phosphorylation signatures within the serine/threonine clusters of the C-terminal tail of CCR7 were found to govern downstream signaling outcomes. Collectively, these results reveal a mechanism reliant on both disulfide bond stability and phosphorylation patterns through which hBD3 differentially regulates CCR7 function, providing novel insights into ligand-specific receptor modulation and potential therapeutic strategies for CCR7-mediated malignancies.