Targeting PD-1/PD-L-1 immune checkpoint inhibition for cancer immunotherapy: success and challenges The PD-1/PD-L-1 immune checkpoint is a critical target in cancer immunotherapy, as its inhibition can enhance T-cell activity and improve anti-tumor responses. However, the use of monoclonal antibodies (mAbs) targeting this pathway has limitations, including poor tumor penetration, high costs, and immune-related side effects. Recent advancements in small molecule inhibitors (SMIs) offer promising alternatives, as they can overcome these limitations by providing longer half-lives, lower costs, and better cell penetration. SMIs have shown potential in blocking the PD-1/PD-L-1 axis and have been developed using various structural scaffolds, with biphenyl-based scaffolds being the most studied. The PD-1/PD-L-1 pathway is regulated by various post-translational modifications, including glycosylation, ubiquitination, and phosphorylation, which influence its expression and function. Understanding these mechanisms is crucial for developing effective therapies. PD-1/PD-L-1 interactions can occur in both cis and trans configurations, with cis interactions potentially inhibiting the trans interaction and reducing the effectiveness of immunotherapy. Therefore, strategies to overcome these cis interactions are essential for improving treatment outcomes. Several SMIs have been developed and tested for their ability to inhibit the PD-1/PD-L-1 axis. These include compounds such as BMS-8, BMS-202, and CA-170, which have shown promising results in preclinical studies. Additionally, new compounds such as INCB086550 and PDI-1 have been identified as potential inhibitors of the PD-1/PD-L-1 pathway. These compounds have demonstrated the ability to enhance T-cell activity, reduce tumor growth, and improve immune responses. Despite the progress in developing SMIs, challenges remain in optimizing their efficacy and minimizing side effects. The development of bifunctional small molecules that can target multiple pathways simultaneously is an emerging area of research, with the aim of improving the effectiveness of cancer immunotherapy. Overall, the continued exploration of SMIs and their potential as alternative therapies to mAbs is crucial for advancing cancer immunotherapy and improving patient outcomes.Targeting PD-1/PD-L-1 immune checkpoint inhibition for cancer immunotherapy: success and challenges The PD-1/PD-L-1 immune checkpoint is a critical target in cancer immunotherapy, as its inhibition can enhance T-cell activity and improve anti-tumor responses. However, the use of monoclonal antibodies (mAbs) targeting this pathway has limitations, including poor tumor penetration, high costs, and immune-related side effects. Recent advancements in small molecule inhibitors (SMIs) offer promising alternatives, as they can overcome these limitations by providing longer half-lives, lower costs, and better cell penetration. SMIs have shown potential in blocking the PD-1/PD-L-1 axis and have been developed using various structural scaffolds, with biphenyl-based scaffolds being the most studied. The PD-1/PD-L-1 pathway is regulated by various post-translational modifications, including glycosylation, ubiquitination, and phosphorylation, which influence its expression and function. Understanding these mechanisms is crucial for developing effective therapies. PD-1/PD-L-1 interactions can occur in both cis and trans configurations, with cis interactions potentially inhibiting the trans interaction and reducing the effectiveness of immunotherapy. Therefore, strategies to overcome these cis interactions are essential for improving treatment outcomes. Several SMIs have been developed and tested for their ability to inhibit the PD-1/PD-L-1 axis. These include compounds such as BMS-8, BMS-202, and CA-170, which have shown promising results in preclinical studies. Additionally, new compounds such as INCB086550 and PDI-1 have been identified as potential inhibitors of the PD-1/PD-L-1 pathway. These compounds have demonstrated the ability to enhance T-cell activity, reduce tumor growth, and improve immune responses. Despite the progress in developing SMIs, challenges remain in optimizing their efficacy and minimizing side effects. The development of bifunctional small molecules that can target multiple pathways simultaneously is an emerging area of research, with the aim of improving the effectiveness of cancer immunotherapy. Overall, the continued exploration of SMIs and their potential as alternative therapies to mAbs is crucial for advancing cancer immunotherapy and improving patient outcomes.