Tumor cell ligands for activating and death-inducing NK receptors

Tumor cell ligands for activating and death-inducing NK receptors are a diverse set of cell-surface proteins that signal the presence of cellular stress or transformation to the innate immune system. This group includes NKG2D ligands such as MHC class I polypeptide-related sequence A (MICA), MICB, and UL16-binding proteins (ULBP1-6), as well as DNAM-1 ligands like Poliovirus receptor (CD155) and Nectin-2 (CD112). Additionally, it encompasses death receptors like TRAIL receptor 1 (DR4) and TRAIL receptor 2 (DR5) which, when engaged by their respective ligands, trigger programmed cell death (Duan et al., 2021, Frontiers in Immunology). These ligands are typically absent or expressed at low levels in healthy tissues but are significantly upregulated in various cancers due to DNA damage, oxidative stress, or oncogenic signaling (Shimasaki et al., 2020, Nature Reviews Drug Discovery). In therapeutic contexts, these ligands are targeted to enhance NK cell-mediated immunosurveillance and direct tumor lysis. Strategies include the development of agonistic antibodies for death receptors, bispecific NK-cell engagers (BiKEs) that bridge these ligands to NK cell activating receptors, and CAR-NK cells engineered to recognize these stress-induced markers. A major challenge in targeting these molecules is the tumor-mediated proteolytic shedding of ligands like MICA and MICB, which generates soluble decoys that inhibit NK cell function and facilitate immune evasion (Waldhauer and Steinle, 2008, Cancer Research). Current research focuses on preventing this shedding or overcoming the inhibitory environment created by soluble ligands to restore effective anti-tumor immunity.

Other names

NK cell activating ligandsStress-induced ligandsNKG2D ligandsDNAM-1 ligandsDeath receptor ligandsNK cell receptor ligands

Activation of NK cell-mediated cytotoxicity and induction of extrinsic apoptosis in tumor cells (Duan et al., 2021; von Karstedt et al., 2017).