Viscoelastic Niches Shape γδ T Cell Phenotype and Effector Function

γδ T-cells, which are enriched in epithelial tissues, have been used in cancer therapy because of their capacity for rapid, MHC-independent cytotoxicity. However, current paradigms largely overlook the role of tissue mechanical cues in regulating γδ T-cell function. Here, we investigated how matrix viscoelasticity modulates γδ T-cell migration, differentiation state, phenotype, and function, using a tunable collagen-based gel system. Slow-relaxing matrices preserved a less differentiated phenotype, reduced migration, and increased FAS and PD-1 expression. Despite increased PD-1 expression, these cells remained functional, demonstrated by high levels of TNF-α and IFN-γ relative to PD-1-negative cells. Proteomic analysis revealed that γδ T-cells respond to changes in viscoelasticity through actin remodeling and shifts in metabolic machinery. Functionally, cells encapsulated in slow-relaxing gels showed improved control of tumor growth in an aggressive HCT116 tumor model. Together, these findings establish matrix viscoelasticity as an important regulator of post-thymic γδ T-cell differentiation and function.