Functionally, under the influence of TGF-β/SMAD3/HDAC-mediated epigenetic reprogramming, metabolic stress (such as lactate-induced mTORC1 inhibition) and spatial cues (for instance, the accumulation of PD-L1+ NK cells in the cores of EBV+ gastric cancer), NK cells shift from cytotoxic effectors to immunosuppressive regulators. The gene discussed is SMAD3; the disease is gastric cancer.