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

Colorectal cancer (CRC) is a major global health burden, driven by complex genetic and epigenetic alterations and an immunosuppressive tumor microenvironment (TME). The PD‐1/PD‐L1 immune checkpoint plays a central role in CRC immune evasion, making it a critical therapeutic target. Immune checkpoint inhibitors (ICIs) have achieved notable efficacy in microsatellite instability‐high (MSI‐H) or mismatch repair‐deficient (dMMR) CRC, attributed to their high neoantigen burden. However, most CRC cases are microsatellite stable (MSS) and exhibit limited responsiveness to PD‐1/PD‐L1 blockade due to immune escape mechanisms, including β 2‐microglobulin and JAK/STAT mutations, HLA loss, and infiltration of regulatory T cells and myeloid‐derived suppressor cells. Small‐molecule inhibitors targeting PD‐1/PD‐L1 are emerging as promising alternatives to monoclonal antibodies, offering advantages such as oral administration, improved tissue penetration, and modulation of upstream and downstream signaling pathways. Compounds such as MPT0G612, Panaxadiol, Butyrate, Licochalcone A, and Demethylzeylasteral exhibit antitumor effects by suppressing PD‐L1 expression, promoting its degradation, or enhancing T cell infiltration in the TME. Early clinical trials of CA‐170, INCB086550, and ASC61 indicate encouraging activity in solid tumors, including CRC. This review summarizes the role of the PD‐1/PD‐L1 axis in CRC and discusses the therapeutic potential and future prospects of small‐molecule inhibitors as next‐generation immunotherapies for CRC.