Gamma Delta T Cells in the Tumour Microenvironment: A Double-Edged Sword Publisher Pubmed



Hayati MJ ; Yaghmoorian Khojini J ; Khara F ; Heydari A ; Vousooghi N ; Abootorabi SMS ; Barkhordar M ; Mousavi MJ
Source: Immunology Published:2025

Abstract

Gamma delta (γδ) T cells represent a distinct group of lymphocytes capable of functioning in both pro-tumorigenic and anti-tumorigenic capacities inside the tumour microenvironment (TME). Their unique ability for MHC-independent recognition of stress-induced antigens enables swift immunosurveillance, positioning them as a double-edged sword in cancer immunosurveillance. This review critically investigates this dichotomy, analysing their potent tumour-suppressive roles, which are primarily driven by subsets like Vγ9Vδ2 T cells through cytotoxic mechanisms such as perforin and granzyme release and the secretion of pro-inflammatory cytokines like interferon-gamma (IFN-γ). Conversely, we explore their tumour-promoting functions, wherein subsets such as IL-17-producing Vδ1 T cells can foster an immunosuppressive milieu, angiogenesis, and immune evasion. The function of γδ T cells is extensively examined, emphasising how the TME critically dictates this functional polarisation. This duality presents both a significant challenge and a promising opportunity for cancer immunotherapy. Future investigations and emerging therapeutic strategies are discussed, including the use of adoptive cell therapies with CAR-γδ T cells and combination approaches with immune checkpoint inhibitors, which aim to overcome the TME's suppressive barriers. A deeper understanding of the molecular switches that govern γδ T cell function is paramount for devising effective next-generation therapies that can exploit their full anti-cancer potential. © 2025 Elsevier B.V., All rights reserved.