Immune suppression largely contributes to cancer occurrence and progression. The programmed cell death protein 1 (PD-1, also known as PDCD1 and CD279) was originally identified by Ishida et al. in apoptotic mouse T-cell tumors [1]. PD-1 is a transmembrane protein belonging to the CD28/CTLA-4 superfamily. It is widely expressed at the surface of activated T cells, B cells, monocytes, and other immune cells, and negatively regulates human immune response through binding with its two ligands, namely programmed cell death 1 ligands (PD-L1 or PD-L2). PD-L1 (B7-H1; CD274) and PD-L2 (B7-DC; CD273) belong to the B7 family of T cell co-inhibitory molecules. PD-L1 is widely expressed in antigen-presenting cells and tissues, such as heart and lung [2, 3]. The interaction of PD-1 with PD-L1 or PD-L2 provides inhibitory signals responsible for inhibiting T cell signaling, mediating the mechanisms of tolerance, and providing immune homeostasis. Therefore, PD-1 suppresses autoimmunity and prevents the occurrence of autoimmune diseases. In addition, PD-L1 or PD-L2 expressed by cancer cells binds to PD-1 on the surface of T cells, thereby inhibiting T cell activation and leading to cancer immune escape [4]. Numerous studies revealed that PD-L1 expression is very high in lung cancer, melanoma, glioma, breast cancer and other malignant tumor cells, forming an immunosuppressive tumor microenvironment [5].
PD-1 mainly consists of extracellular IgV-like domain region, hydrophobic transmembrane region and cytoplasmic region, and the tail of the cytoplasmic region has immunoreceptor tyrosine-based inhibitory motif (ITIM) and immunoreceptor tyrosine-based switch motif (ITSM) [6, 7], which is an important structural basis for PD-1 to transmit inhibitory signals and perform immunosuppressive functions. PD-L1 is structurally similar to PD-1 and is more conserved and widely expressed than PD-L2 [8], so it plays the leading effect in tumor cells immune evasion. In recent years, antagonistic antibodies against PD-1 or PD-L1 have been approved by the FDA to treat cancer, opening a new chapter in tumor immunotherapy across the era [9].
Anti-PD-1/PD-L1 inhibitors have become effective immune checkpoint inhibitors (ICIs) and are rapidly becoming the standard therapy for various cancers. Tumor immunotherapy aims to block the activity of inhibitory immune checkpoint proteins and promote T cell activation to achieve anti-tumor immune effects [10]. Owing to their safety and precision, these inhibitors hold significant promise in tumor immunotherapy. Research indicates that the PD-1/PD-L1 pathway plays a crucial role in regulating autoimmunity responses and peripheral tolerance. Notably, anti-PD-1/PD-L1 immunotherapy can effectively block the PD-1/PD-L1 signaling pathway, restore T cell activity, enhance anti-tumor immunity, and then eliminate tumor cells [11, 12]. Therefore, the discovery of multiple immunotherapies, such as PD-1 and PD-L1 inhibitors, has significant clinical implications for tumor-specific immunotherapy.
