Remodelling hypoxic TNBC microenvironment restores antitumor efficacy of Vγ9Vδ2 T cell therapy

BACKGROUND: γδ T cells have emerged as pivotal regulators within the breast cancer tumour microenvironment (TME) and represent a promising therapeutic strategy for late-stage and metastatic breast cancer. In recent years, our research has focused on leveraging allogeneic Vγ9Vδ2 T cells as a novel approach to treat advanced cancers, including triple-negative breast cancer (TNBC). However, the varying clinical outcomes of this therapy have prompted us to investigate the diverse roles of γδ T cells within the TNBC microenvironment and to explore strategies for enhancing therapeutic efficacy through microenvironmental remodelling. METHODS: Data from TCGA, publicly available scRNA-seq datasets and a series of experiments including flow cytometry, atomic force microscopy, confocal laser scanning microscopy, mouse model and others were applied to examine the functional heterogeneity of γδ T cells in TNBC, non-TNBC, and healthy individuals. RESULTS: γδ T cells serve as predictive markers of better prognosis in breast cancer. In TNBC tumours, γδ T cells exhibited heightened expression of genes linked to both effector and inhibitory molecules, alongside a significant upregulation of glycolytic activity-patterns not observed in non-TNBC or normal breast tissues. Further analysis demonstrated that hypoxic conditions in the TNBC microenvironment likely contribute to these metabolic changes, leading to upregulation of inhibitory checkpoints and downregulation of effector functions in γδ T cells. Importantly, we showed that suppressing HIF-1 signalling using PX478 enhanced the antitumor efficacy of Vδ2(+)γδ T cell therapy in TNBC-bearing mice. DISCUSSION: This work underscores that remodelling the hypoxic TNBC microenvironment can restore the antitumor activity of Vγ9Vδ2 T cell therapy. Our findings offer a compelling new adjuvant strategy to improve the outcomes of Vγ9Vδ2 T cell-based therapies for advanced breast cancer treatment.