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

The role of gamma S Tcells in antitumor responses has gained significant attention due to their major histocompatibility complex (MHC)-independent killing mechanisms, which are functionally distinct from conventional alpha beta T cells. Notably, gamma S tumor- infiltrating lymphocytes (TILs) have been identified as favorable prognostic markers in various cancers. However, the gamma S TIL subsets, including VS1, VS2, and VS3, 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. VS1 TILs appear to be mainly activated by gamma S T-cell receptor (TCR) signaling, whereas VS2 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 gamma S T cells, gamma S T-cell engagers, and gamma S 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 gamma S T-cell therapies as a transformative platform for cancer treatment. Here, we review recent findings on the prognostic significance of human gamma S T cells, their phenotypic characteristics, and advances in gamma S T-cell therapies, offering valuable insights for the development of novel cancer immunotherapies. (c) 2025 The Authors. Published by Elsevier Inc. on behalf of Korean Society for Molecular and Cellular Biology. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).