Watanabe_2026_Mol.Med.Rep_33_

The present review focuses on the molecular functions of prostate-specific membrane antigen (PSMA) as a biologically active protein. Its clinical use as a positron emission tomography imaging marker or radioligand therapy target is beyond the scope of the current review. The role of PSMA (also known as folate hydrolase 1/glutamate carboxypeptidase II/N-acetylated-alpha-linked acidic dipeptidase) has progressed from that of a prostate cancer biomarker to a functional driver of tumor biology. Structurally, PSMA is a type II transmembrane glycoprotein with glutamate carboxypeptidase and folate hydrolase activities, linking glutamate and one-carbon metabolism to proliferation, redox balance and epigenetic regulation. PSMA undergoes clathrin-dependent endocytosis and interacts with various scaffolding proteins, such as filamin A and receptor for activated C kinase 1, which are properties that underlie its functional role as a molecular signaling hub, in addition to being a therapeutic entry point. Its expression is dynamically regulated by androgen receptor signaling, NF-kappaB activation and epigenetic modifiers, contributing to intra-patient heterogeneity and treatment resistance. PSMA expression is not restricted to prostate epithelium but is also expressed in tumor-associated endothelium across multiple malignancies, where it can promote angiogenesis through integrin/PI3K-AKT-mTOR signaling and paracrine induction by extracellular vesicles. These molecular functions can result in immune exclusion, stromal activation and neuronal interactions, positioning PSMA as a key regulator of the tumor microenvironment. Although PSMA-targeted imaging and therapies have demonstrated substantial clinical utility, understanding the biological basis of the function of PSMA is essential for interpreting the heterogeneous clinical responses and for designing next-generation therapeutic strategies in association with this protein. By integrating enzymatic activity, non-enzymatic scaffold signaling and tumor microenvironmental regulatory information, the present review provides a functional framework in the PSMA biology field and discusses how these molecular properties can be leveraged to develop novel rational and effective PSMA-targeted interventions.