Small-Molecule Inhibitors Targeting PD-1/PD-L1 in Colorectal Cancer: Mechanisms, Challenges, and Clinical Prospects

Area of Science:

• Oncology
• Immunology
• Pharmacology

Background:

• Colorectal cancer (CRC) presents a significant global health challenge, characterized by genetic alterations and an immunosuppressive tumor microenvironment (TME).
• The PD-1/PD-L1 immune checkpoint is crucial for CRC immune evasion, representing a key therapeutic target.
• While immune checkpoint inhibitors (ICIs) benefit MSI-H/dMMR CRC, MSS CRC shows limited response due to immune escape mechanisms.

Purpose of the Study:

• To review the role of the PD-1/PD-L1 axis in colorectal cancer.
• To discuss the therapeutic potential of small-molecule inhibitors targeting PD-1/PD-L1 in CRC.
• To explore future prospects of these inhibitors as next-generation immunotherapies for CRC.

Main Methods:

• Literature review summarizing current research on PD-1/PD-L1 axis in CRC.
• Analysis of small-molecule inhibitors targeting PD-1/PD-L1 and their mechanisms of action.
• Evaluation of early clinical trial data for small-molecule PD-1/PD-L1 inhibitors in solid tumors, including CRC.

Main Results:

• Small-molecule inhibitors offer advantages over monoclonal antibodies, including oral administration and better tissue penetration.
• Several compounds (e.g., MPT0G612, Panaxadiol, Butyrate) demonstrate antitumor effects by modulating PD-L1 expression or T cell infiltration.
• Early clinical trials of agents like CA-170, INCB086550, and ASC61 show promising activity in solid tumors, including CRC.

Conclusions:

• Small-molecule inhibitors targeting PD-1/PD-L1 represent a promising therapeutic strategy for colorectal cancer, particularly for MSS tumors.
• These inhibitors can overcome immune escape mechanisms and enhance the efficacy of cancer immunotherapy.
• Further clinical development of small-molecule PD-1/PD-L1 inhibitors holds significant potential for advancing CRC treatment.