Deciphering the dual role of γδ T cells in the non-small cell lung cancer microenvironment: mechanistic insights and therapeutic frontiers

Background Lung cancer is the leading cause of cancer-related death worldwide, and non-small cell lung cancer accounts for approximately 85% of all cases. Although immune checkpoint inhibitors have transformed the therapeutic landscape, downregulation of the major histocompatibility complex and chronic immunosuppression in the tumor microenvironment frequently limit the efficacy of conventional T cell immunotherapy. Gamma delta T cells, unconventional lymphocytes enriched in pulmonary mucosa, provide surveillance independent of the major histocompatibility complex; however, their functional plasticity creates a paradoxical double-edged sword in non-small cell lung cancer. Main body Cytotoxic type 1 gamma delta T cells eradicate tumors through perforin and granzyme release and interferon-gamma secretion, whereas commensal microbiota-driven interleukin-1 beta and interleukin-23 can subvert tissue-resident subsets into pro-tumorigenic type 17 cells that accelerate cancer progression via interleukin-17-mediated neutrophil recruitment. This review integrates mechanistic insights into this dichotomy, emphasizing the butyrophilin 3A1/2A1 phosphoantigen recognition axis, metabolic reprogramming under nutrient deprivation, and microbiota-immune crosstalk. We further examine how the hostile lung microenvironment imposes metabolic, epigenetic, and physical barriers that impair gamma delta T cell efficacy, and survey emerging engineering strategies including allogeneic cellular products, epigenetic priming, and combination approaches. Conclusion We propose a translational roadmap integrating allogeneic off-the-shelf cellular engineering, metabolic priming to reverse immune senescence, and microbiota-directed polarization to stabilize durable anti-tumor phenotypes. These strategies aim to overcome immune escape caused by impaired antigen presentation and advance precision immunotherapy for non-small cell lung cancer.