Human γδ T cells in the tumor microenvironment: Key insights for advancing cancer immunotherapy

The role of γδ T cells in antitumor responses has gained significant attention due to their unique major histocompatibility complex (MHC)-independent killing mechanisms, which distinguish them from conventional αβ T cells. Notably, γδ tumor-infiltrating lymphocytes (TILs) have been identified as favorable prognostic markers in various cancers. However, γδ TIL subsets, including Vδ1, Vδ2, and Vδ3, exhibit distinct prognostic implications and phenotypes from one another within the tumor microenvironment (TME). Although the underlying mechanisms remain unclear, recent studies suggest that these subset-specific differences may arise from divergent activation pathways. Vδ1 TILs appear to be mainly activated by γδ T-cell receptor (TCR) signaling, whereas Vδ2 TILs seem to rely on alternative pathways, such as natural killer (NK) receptor-mediated activation. In addition to phenotypic studies, γδ T cell-based immunotherapies are being actively developed using innovative approaches including engineered γδ T cells, γδ T cell engager molecules, and γδ TCR-based T cell therapies. Despite these advancements, challenges such as functional heterogeneity and limited in vivo persistence remain unresolved. Overcoming these obstacles could position γδ T cell therapies as a transformative platform for cancer immunotherapy. This review explores recent findings on the role of γδ T cells as prognostic markers, their phenotypic characteristics within the human TME, and recent advancements in γδ T cell-based cancer immunotherapies, offering valuable insights for the development of novel therapeutic strategies.