The article "Targeting PD-1/PD-L-1 Immune Checkpoint Inhibition for Cancer Immunotherapy: Success and Challenges" by Sadique A. Javed, Asim Najmi, Waquar Ahsan, and Khalid Zoghebi reviews the progress and challenges in the development of PD-1/PD-L-1 inhibitors for cancer immunotherapy. The programmed death-1 receptor (PD-1) and its ligand PD-L-1 play a crucial role in suppressing T-cell activity in the tumor microenvironment, leading to compromised anticancer immunity. Monoclonal antibodies (mAbs) targeting the PD-1/PD-L-1 axis have shown remarkable clinical success, but their therapeutic use is limited due to poor clinical responses in some patients, low tumor penetration, high production costs, and immune-related side effects. To address these issues, researchers have turned to small molecule inhibitors (SMIs) that offer advantages such as longer half-lives, lower costs, greater cell penetration, and potential oral administration. The article discusses the development of SMIs, including the exploration of various structural scaffolds, particularly biphenyl-based scaffolds, and their potential as effective therapeutics. The review also highlights the importance of understanding the mechanisms of PD-1/PD-L-1 expression and interaction, as well as the role of post-translational modifications in regulating these pathways. Finally, the article explores the therapeutic implications of PD-1/PD-L-1 blockage, the challenges associated with mAbs, and the potential of SMIs in overcoming these limitations. The authors conclude by emphasizing the need for further research to develop novel PD-1/PD-L-1 inhibitors that can enhance the effectiveness of cancer immunotherapy.The article "Targeting PD-1/PD-L-1 Immune Checkpoint Inhibition for Cancer Immunotherapy: Success and Challenges" by Sadique A. Javed, Asim Najmi, Waquar Ahsan, and Khalid Zoghebi reviews the progress and challenges in the development of PD-1/PD-L-1 inhibitors for cancer immunotherapy. The programmed death-1 receptor (PD-1) and its ligand PD-L-1 play a crucial role in suppressing T-cell activity in the tumor microenvironment, leading to compromised anticancer immunity. Monoclonal antibodies (mAbs) targeting the PD-1/PD-L-1 axis have shown remarkable clinical success, but their therapeutic use is limited due to poor clinical responses in some patients, low tumor penetration, high production costs, and immune-related side effects. To address these issues, researchers have turned to small molecule inhibitors (SMIs) that offer advantages such as longer half-lives, lower costs, greater cell penetration, and potential oral administration. The article discusses the development of SMIs, including the exploration of various structural scaffolds, particularly biphenyl-based scaffolds, and their potential as effective therapeutics. The review also highlights the importance of understanding the mechanisms of PD-1/PD-L-1 expression and interaction, as well as the role of post-translational modifications in regulating these pathways. Finally, the article explores the therapeutic implications of PD-1/PD-L-1 blockage, the challenges associated with mAbs, and the potential of SMIs in overcoming these limitations. The authors conclude by emphasizing the need for further research to develop novel PD-1/PD-L-1 inhibitors that can enhance the effectiveness of cancer immunotherapy.