NKG2D and its ligands in cancer

•NKG2D pathway is significant for both innate and adoptive tumor immunity.•Soluble and membrane-bound NKG2D ligands confer opposite role in tumor immunity.•Soluble NKG2D ligands are immune suppressive in cancer patients.•Harnessing NKG2D pathway is a viable avenue for cancer immunotherapy.•Targeting soluble NKG2D ligands is a viable approach for harnessing NKG2D pathway. NKG2D is an activating immune receptor expressed by NK and effector T cells. Induced expression of NKG2D ligand on tumor cell surface during oncogenic insults renders cancer cells susceptible to immune destruction. In advanced human cancers, tumor cells shed NKG2D ligand to produce an immune soluble form as a means of immune evasion. Soluble NKG2D ligands have been associated with poor clinical prognosis in cancer patients. Harnessing NKG2D pathway is considered a viable avenue in cancer immunotherapy over recent years. In this review, we will discuss the progress and perspectives.