Programmed Death-Ligand 1 (PD-L1) is an immune checkpoint molecule expressed on antigen-presenting cells and various cancer cells, critically involved in modulating T-cell-mediated immune responses. Its interaction with programmed cell death protein 1 (PD-1) on activated T cells delivers inhibitory signals that suppress cytotoxic activity and promote immune tolerance-a mechanism exploited by malignancies to evade immune surveillance. Elevated PD-L1 expression has been documented across multiple tumor types including non-small cell lung carcinoma, melanoma, and gastrointestinal cancers, correlating with advanced disease progression and poorer prognostic outcomes.
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.