The PD-1 checkpoint pathway, involving the receptor programmed cell death 1 (PD-1) and its ligands PD-L1 and PD-L2, plays a crucial role in maintaining peripheral tolerance by inhibiting T-cell activation. Tumors and chronic infections exploit this pathway to escape immune responses. Therapies targeting PD-1 and its ligands have shown remarkable efficacy in various cancers, revolutionizing cancer treatment. The molecular mechanisms underlying PD-1's effects on T cells are complex, involving signaling pathways such as PI3K-Akt, Ras-MEK-ERK, and p38 MAP kinase. PD-1 also influences T-cell metabolism, leading to altered differentiation profiles and functional properties. The clinical implications of PD-1/PD-L1/PD-L2 blockade include the expansion of tumor-infiltrating CD8+ T cells and the activation of neoantigen-specific responses. However, therapeutic targeting of the PD-1 checkpoint can lead to autoimmune-like side effects, highlighting the need for understanding and managing these toxicities. The genomic landscape of tumors, particularly the presence of neoantigens, influences the efficacy of checkpoint immunotherapy. Further research into the biochemical and signaling effects of PD-1 will help optimize treatment strategies and address the challenges of autoimmune-like responses.The PD-1 checkpoint pathway, involving the receptor programmed cell death 1 (PD-1) and its ligands PD-L1 and PD-L2, plays a crucial role in maintaining peripheral tolerance by inhibiting T-cell activation. Tumors and chronic infections exploit this pathway to escape immune responses. Therapies targeting PD-1 and its ligands have shown remarkable efficacy in various cancers, revolutionizing cancer treatment. The molecular mechanisms underlying PD-1's effects on T cells are complex, involving signaling pathways such as PI3K-Akt, Ras-MEK-ERK, and p38 MAP kinase. PD-1 also influences T-cell metabolism, leading to altered differentiation profiles and functional properties. The clinical implications of PD-1/PD-L1/PD-L2 blockade include the expansion of tumor-infiltrating CD8+ T cells and the activation of neoantigen-specific responses. However, therapeutic targeting of the PD-1 checkpoint can lead to autoimmune-like side effects, highlighting the need for understanding and managing these toxicities. The genomic landscape of tumors, particularly the presence of neoantigens, influences the efficacy of checkpoint immunotherapy. Further research into the biochemical and signaling effects of PD-1 will help optimize treatment strategies and address the challenges of autoimmune-like responses.