Transforming growth factor-beta receptor type 2 (TGFBR2) (TGFBR2)

Transforming growth factor-beta receptor type 2 (TGFBR2) is a transmembrane serine/threonine kinase receptor that, upon binding TGF-beta ligands, initiates a signaling cascade that is highly immunosuppressive to natural killer (NK) cells (Viel et al., 2016; PubMed: 26883474). In the tumor microenvironment, this pathway triggers the phosphorylation of SMAD2 and SMAD3, which translocate to the nucleus to repress the expression of activating receptors like NKG2D and NKp30 (Wilson et al., 2011; PubMed: 21931811). TGF-beta signaling also inhibits NK cell effector functions, including the production of interferon-gamma, granzyme B, and perforin, thereby facilitating tumor immune evasion (Otegbeye et al., 2018; PubMed: 29346457). Furthermore, it suppresses NK cell metabolism by inhibiting the mTOR pathway, which is essential for the metabolic reprogramming required for optimal anti-tumor activity (Viel et al., 2016; Frontiers in Immunology, 2020). Chronic exposure to TGF-beta can even drive the transdifferentiation of NK cells into non-cytotoxic, ILC1-like cells (bioRxiv, 2024). Therapeutic targeting of this axis involves small molecule inhibitors of the receptor kinase, neutralizing antibodies against the ligands, and genetic engineering of NK cells to express dominant-negative receptors or to delete the TGFBR2 gene (Kaufman et al., 2024; PMC: 5812584). These interventions are designed to protect NK cells from TGF-beta-mediated inhibition, thereby enhancing their anti-tumor potency in various cancers (R&D Systems, 2018; PMC: 7875857).

Other names

TGF-beta signaling in NK cellsTGF-beta receptor type IITGFBR2TGFR-2Transforming growth factor-beta signaling pathway in natural killer cells

Inhibition of TGF-beta receptor kinase activity, neutralization of TGF-beta ligands, or genetic disruption of receptor expression to prevent immunosuppressive signaling in NK cells (PubMed: 29346457, 21931811).