γδ T Cells as a Platform for Immunotherapy: From Biological Principles to Clinical Translation.

Abstract

Background: γδ T cells are emerging as a promising immunotherapy platform because they combine rapid innate-like effector activity with adaptive immune features and recognize stress-associated signals in a largely MHC-independent manner. Their clinical utility, however, is constrained by pronounced heterogeneity in subset composition, tissue localization, and functional state.Objective: This review aims to summarize the biological principles governing γδ T-cell development, classification, and antigen recognition and to examine how their context-dependent functions inform therapeutic design.Methods: We integrated current evidence on γδ T-cell biology across cancer, infection, and autoimmunity and evaluated the major translational strategies currently being developed.Results: Current strategies include in vivo activation, adoptive transfer, combination regimens, engineered γδ T-cell products, and cell-free approaches such as γδ T-cell-derived extracellular vesicles. However, clinical translation remains limited by product heterogeneity, insufficient expansion and persistence, and incomplete mechanistic resolution.Conclusion: Future development should prioritize mechanism-guided engineering, biomarker-informed development, and better-designed clinical studies.