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Translational Therapeutics

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

Abstract

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.

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Fig. 1: Bulk-RNA analysis of immune cell infiltration in breast cancer based on TCGA database.
Fig. 2: Single-cell transcriptome of breast cancer tissue-infiltrating γδ T cells.
Fig. 3: Functional analyses of single cell RNA-seq and bulk RNA-seq of breast cancer tissue-infiltrating γδ T cells.
Fig. 4: Metabolic and biophysical characterisation of γδ T cells in the context of breast cancer cell challenge.
Fig. 5: Transcription factor analysis of tissue-infiltrating γδ T cells.
Fig. 6: HIF-1α associates with metabolic rewiring of γδ T cells in TNBC.
Fig. 7: In vitro and in vivo validation of HIF-1α in regulating the cytotoxicity of γδ T cells.

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Data availability

Data are provided within the manuscript or supplementary information files.

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Acknowledgements

We also thank Dr. Qixin Chen and colleagues from the Pangu MedTech (Guangzhou) for their assistance with scRNA-seq data analysis.

Funding

This work is supported by the National Natural Science Foundation of China (82002787) and the Natural Science Foundation of Guangdong Province of China (2025A1515010628) (YH). YZW is supported by the National Natural Science Foundation of China (32270950), the Natural Science Foundation of Guangdong Province of China (2024A1515010551), the Startup Foundation of the Zhuhai People’s Hospital (YNXM20210305), and partially by the Key Program of the National Natural Science Foundation of China (32030036). XH is supported by the Science and Technology Projects in Guangzhou (202201020050), the Guangdong Medical Science and Technology Research Fund Project (A2023138), and the Beijing Science and Technology Innovation Medical Development Foundation (KC2023-JX-0270-03).

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Contributions

Work supervision and design: YH and YZW. Experiments: YH, YYJ, YZW and QLH. Clinical samples and data collection: YH, YYJ, XH, DL, WHH and MGF. Data analysis and discussion: YH, YZW and YYJ. Mouse model: YYJ, QLH and WFW. Manuscript writing and revision: YH, YZW and YYJ. All authors approved the final version of manuscript.

Corresponding authors

Correspondence to Yangzhe Wu, Minggang Fu, Xin Huang or Yi Hu.

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The animal related experiment was approved by the Jinan University Laboratory Animal Ethics Committee (#20210712-28).

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Jing, Y., Wu, Y., Hu, Q. et al. Remodelling hypoxic TNBC microenvironment restores antitumor efficacy of Vγ9Vδ2 T cell therapy. Br J Cancer (2025). https://doi.org/10.1038/s41416-025-03045-x

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