PSMA (Prostate-specific membrane antigen, also known as Glutamate carboxypeptidase II (GCPII) or N-acetyl-L-aspartyl-L-glutamate peptidase I (NAALADase I)), is a type II transmembrane zinc metallopeptidase and is encoded in humans by the folate hydrolase 1 (FOLH1) gene. Human PSMA contains 750 amino acids and weighs around 84 kDa. The PSMA protein has a 3-part structure involving a 19-amino-acid internal portion, a 24-amino-acid transmembrane portion and a 707-amino-acid external portion. PSMA is a unique transmembrane glycoprotein over-expressed manifold on prostate cancer and neovasculature of most of the solid tumors, but not in the vasculature of the normal tissues. This specific expression of PSMA thereby makes it an important biomarker in the majority of prostate cancers.
4-1BB (also known as CD137 or TNFRSF9) is a type I transmembrane glycoprotein belonging to the tumor necrosis factor receptor superfamily (TNFRSF). It consists of 255 amino acids with a molecular weight of ~28 kDa, featuring an extracellular domain containing four cysteine-rich motifs, a transmembrane helix, and an intracellular domain critical for downstream signaling. Primarily expressed on activated T cells and natural killer (NK) cells, 4-1BB is upregulated upon T-cell receptor engagement and interacts with its ligand 4-1BBL, which is predominantly displayed on antigen-presenting cells (APCs) like dendritic cells and macrophages. This receptor-ligand interaction recruits TRAF adaptor proteins (TRAF1, TRAF2, TRAF3) to form signalosomes, activating NF-κB and MAPK pathways that enhance T-cell proliferation, cytotoxic activity, and pro-inflammatory cytokine production, while suppressing apoptosis through upregulated anti-apoptotic proteins like Bcl-2. As a pivotal co-stimulatory molecule in adaptive immunity, 4-1BB has emerged as a promising target for cancer immunotherapy.