γδ T cell exhaustion: Opportunities for intervention.

T lymphocytes are the key protective contributors in chronic infection and tumor, but experience exhaustion by persistent antigen stimulation. As an unconventional lineage of T cells, γδ T cells can rapidly response to varied infectious and tumor challenges in a non-MHC-restricted manner and play key roles in immune surveillance via pleiotropic effector functions, showing promising as candidates for cellular tumor immunotherapy. Activated γδ T cells can also acquire exhaustion signature with elevated expression of immune checkpoints, such as PD-1, decreased cytokine production, and functional impairment. However, the exhaustion features of γδ T cells are distinct from conventional αβ T cells. Here, we review the researches regarding the characteristics, heterogeneity, and mechanisms of γδ T cell exhaustion. These studies provide insights into the combined strategies to overcome the exhaustion of γδ T cells and enhance antitumor immunity. Summary sentence: Review of the characteristics, heterogeneity, and mechanisms of γδ T cell exhaustion provides insights into the combined strategies to enhance γδ T cell-based antitumor immunotherapy.