The potential role of PD-1/PD-L1 small molecule inhibitors in colorectal cancer with different mechanisms of action

Colorectal cancer (CRC) remains one of the leading causes of cancer-related death worldwide, with increasing incidence in younger ages highlighting the need for new or alternative therapy, of which is immune checkpoint inhibitors. Antibody-based immune checkpoint inhibitors targeting the interaction between programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) have revolutionized cancer treatment, including CRC. However, the low response rate in CRC highlights the need for additional research and innovative therapies. Small molecule inhibitors have risen as another strategy worth exploring, considering their potential to target a wide array of PD-1/PD-L1-related pathways. This review focuses on the potential of small molecule inhibitors targeting the PD-1/PD-L1 axis in CRC. Exploring various classes of small molecule inhibitors, including those that directly block the PD-1/PD-L1 interaction and others that target upstream regulators or downstream signaling pathways involved in PD-1/PD-L1-mediated immune suppression. Additionally, modulation of post-transcriptional and post-translational processes, thereby influencing the expression, stability, or localization of PD-1/PD-L1 proteins to enhance antitumor immunity, provides a multifaceted treatment approach. By disrupting these pathways, these inhibitors can restore immune system activity against tumor cells, offering new hope for overcoming resistance and improving outcomes in CRC patients who do not respond to conventional immune checkpoint inhibitors (ICIs). Integrating these small molecules into CRC treatment strategies could represent a promising advancement in the battle against the challenging disease.