PD-1 and TIGIT

Class

PD-1/TIGIT bispecific antibody (rilvegostomig, AZD2936)

Pathway

T-cell/NK-cell checkpoint immune inhibition; also frees CD112/CD155 to co-stimulate CD226

PD-1 and TIGIT are inhibitory receptors expressed on T cells and, in the case of TIGIT, also on natural killer (NK) cells. Both act as checkpoints that dampen immune activation once engaged by their respective ligands, a normal safeguard against excessive immune activity that tumors frequently exploit to escape immune attack. PD-1 binds PD-L1/PD-L2 displayed on tumor or stromal cells, delivering an inhibitory signal that suppresses T-cell function. TIGIT binds CD155 and CD112, ligands that can also engage the activating receptor CD226; because TIGIT binds these ligands more avidly, it outcompetes CD226 and blunts costimulation. A bispecific antibody that blocks both PD-1 and TIGIT simultaneously removes two independent brakes on T cells and NK cells and, by freeing CD155/CD112, allows CD226 to deliver a positive costimulatory signal. Because dysfunctional, tumor-infiltrating lymphocytes often co-express both receptors, dual blockade in a single molecule is intended to reactivate exhausted immune cells more effectively than blocking either checkpoint alone, while potentially concentrating activity on cells bearing both targets. This mechanism is broadly relevant across solid tumors where checkpoint-mediated immune evasion limits the effectiveness of single-agent immunotherapy.