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.
OX40 (TNFRSF4/CD134) is a type I transmembrane glycoprotein belonging to the tumor necrosis factor receptor superfamily, comprising 249 amino acids with a 186-residue extracellular domain containing three complete cysteine-rich domains (CRDs) and a partial C-terminal CRD. Its expression is predominantly observed on activated CD4⁺ and CD8⁺ T cells, peaking 48-72 hours post-T cell receptor (TCR) activation, with regulatory enhancement by CD28 co-stimulation, IL-2, IL-4, and TNF signaling. The functional axis revolves around its interaction with OX40 ligand (OX40L/TNFSF4/gp34), a type II transmembrane protein forming homotrimers on antigen-presenting cells (APCs). OX40-OX40L binding initiates receptor clustering and activates multiple downstream pathways including NF-κB, PI3K/Akt, and MAPK cascades. These signals enhance T cell proliferation, survival via anti-apoptotic protein induction (e.g., Bcl-2/Bcl-xL), and cytokine production (notably IL-2), while concurrently suppressing regulatory T cell (Treg) function. Structurally, the interaction involves trimeric OX40L engaging three OX40 molecules through CRD-mediated recognition. This dual modulation enables OX40 to amplify effector T cell responses against tumors and pathogens while breaking immune tolerance via Treg inhibition, positioning it as a critical immunological rheostat.