Folate receptor (FR) (FR)

Folate receptors (FRs) are a family of high-affinity folate-binding glycoproteins anchored to the cell surface via glycosylphosphatidylinositol (GPI) (UniProt, 2024). The family consists of four distinct isoforms: FR-alpha (FOLR1), FR-beta (FOLR2), FR-gamma (FOLR3), and FR-delta (FOLR4), which facilitate the unidirectional transport of folates into cells through receptor-mediated endocytosis (PubMed, 2023). FR-alpha is highly overexpressed in various epithelial malignancies, including ovarian, lung, and breast cancers, while its expression in normal tissues is limited to the apical surfaces of some epithelia, making it an ideal target for selective oncology therapeutics (NIH, 2024). FR-beta is predominantly expressed on myeloid cells, particularly activated macrophages and tumor-associated macrophages (TAMs), providing a unique target for treating inflammatory diseases like rheumatoid arthritis and for modulating the immunosuppressive tumor microenvironment (PubMed, 2022). Therapeutic strategies targeting these receptors include antibody-drug conjugates (ADCs), radiopharmaceuticals, and small molecule-drug conjugates that exploit the receptor's internalizing capacity to deliver cytotoxic payloads directly into diseased cells (StatPearls, 2023). Furthermore, the restricted expression of these receptors in healthy tissues minimizes off-target effects, although specific toxicities like keratopathy remain a concern for certain drug classes (PubMed, 2023).

Other names

Folate-binding proteinFOLRFolate receptor alphaFolate receptor betaFolate receptor gammaFolate receptor deltaFOLR1FOLR2FOLR3FOLR4

The mechanism of action for drugs targeting folate receptors primarily involves high-affinity binding to the extracellular domain, followed by receptor-mediated endocytosis to internalize conjugated payloads such as toxins or radioisotopes. Additionally, monoclonal antibodies targeting these receptors can induce cell death through antibody-dependent cellular cytotoxicity (ADCC) or by interfering with folate-dependent signaling pathways essential for cell proliferation (PubMed, 2023; NIH, 2024).