γδ T Cell-mediated Tumor Immunity is Tightly Regulated by STING and TGF-β Signaling Pathways

The STING pathway plays a critical role in tumor immunosurveillance. However, the precise mechanisms by which STING regulates gamma delta (γδ) T cell function during tumor progression remain unclear. Herein, we find that tumor-derived cyclic GMP-AMP (cGAMP) activates a distinct STING pathway by inducing TBK1-mediated phosphorylation of Eomes in γδ T cells during the early stage of tumor development is demonstrated. This activation leads to interferon-gamma (IFN-γ) production and consequent tumor surveillance. However, at advanced stages of tumor progression, the accumulation of immune-suppressive cytokine transforming growth factor-beta (TGF-β) downregulates STING levels, compromising the function of γδ T cells. Notably, the synergism between TGF-β inhibition and STING agonists effectively counteracts the immunosuppressive tumor microenvironment, thereby augmenting the antitumoral effects of γδ T cells. These findings present a novel mechanism involving STING-mediated IFN-γ production in γδ T cells and hold significant implications for the development of potent immunotherapeutic approaches against cancer.