Mertk: An emerging target in cancer biology and immuno-oncology

Mertk, a type I Receptor Tyrosine Kinase (RTK) and member of the TAM (Tyro3, Axl, and Mertk) family of homologous tyrosine kinases, has important roles in signal transduction both homeostatically on normal cells as well as patho-physiologically on both tumor-associated macrophages and malignant cells by its overexpression in a wide array of cancers. The main ligands of Mertk are Vitamin K-modified endogenous proteins Gas6 and Protein S (ProS1), heterobifunctional modular proteins that bind Mertk via two carboxyl-terminal laminin-like globular (LG) domains, and an N-terminal Gla domain that binds anionic phospholipids, whereby externalized phosphatidylserine (PS) on stressed viable and caspase-activated apoptotic cells is most emblematic. Recent studies indicate that Vitamin K-dependent γ-carboxylation on the N-terminal Gla domain of Gas6 and Protein S is necessary for PS binding and Mertk activation, implying that Mertk is preferentially active in tissues where there is high externalized PS, such as the tumor microenvironment (TME) and acute virally infected tissues. Once stimulated, activated Mertk can provide a survival advantage for cancer cells as well as drive compensatory proliferation. On monocytes and tumor-associated macrophages, Mertk promotes efferocytosis and acts as an inhibitory receptor that impairs host anti-tumor immunity, functioning akin to a myeloid checkpoint inhibitor. In recent years, inhibition of Mertk has been implicated in a dual role to enhance the sensitivity of cancer cells to cytotoxic agents along with improving host anti-tumor immunity with anti-PD-1/PD-L1 immunotherapy. Here, we examine the rationale of Mertk-targeted immunotherapies, the current and potential therapeutic strategies, the clinical status of Mertk-specific therapies, and potential challenges and obstacles for Mertk-focused therapies.