Nonetheless, tumor-intrinsic and microenvironmental mechanisms, including TGF-β/adenosine-driven suppression, hypoxia and metabolic stress, protease-mediated shedding or down-modulation of activating ligands (e.g., MICA/B) that blunt NKG2D signaling, upregulation of HLA-E engaging the inhibitory NKG2A receptor, and ADAM17-dependent cleavage of CD16 that dampens ADCC can attenuate responses and shorten benefit windows, motivating combinations and engineering to enhance persistence, trafficking, and resistance to checkpoint-mediated suppression [10,38,39,40]. This evidence concerns the gene HLA-E and neoplasm.