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

Abstract

The role of γδ T cells in antitumor responses has gained significant attention due to their major histocompatibility complex (MHC)-independent killing mechanisms, which are functionally distinct from conventional αβ T cells. Notably, γδ tumor-infiltrating lymphocytes (TILs) have been identified as favorable prognostic markers in various cancers. However, the γδ TIL subsets, including Vδ1, Vδ2, and Vδ3, exhibit distinct prognostic implications and phenotypes 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, cancer immunotherapies, such as engineered γδ T cells, γδ T-cell engagers, and γδ TCR–based therapies, are under active development. However, despite these advancements, functional heterogeneity and limited persistence within TME remain significant challenges. Overcoming these obstacles could position γδ T-cell therapies as a transformative platform for cancer treatment. Here, we review recent findings on the prognostic significance of human γδ T cells, their phenotypic characteristics, and advances in γδ T-cell therapies, offering valuable insights for the development of novel cancer immunotherapies.