Pharmacological modulation of the PD-1/PD-L1 axis: from immune tolerance in colitis to immune escape in colorectal cancer

R.M. Grimaldi, F.C. Balestrero, A. Meggiolan, M. Serra, A. Ferramosca, C. Travelli

Department of Drug Sciences, University of Pavia, Pavia, Italy. cristina.travelli@unipv.it

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• Pharmacology

In recent years, immune-based therapies, particularly checkpoint inhibitors, have been developed to interfere with tumor immune escape. Among various molecular targets, the PD-1/PD-L1 axis represents a central mechanism of tumor-driven immune evasion and a major target for restoring T-cell-mediated anti-tumor activity. Several blocking monoclonal antibodies have been developed to restore antitumor immunity, and anti-PD-1/PD-L1 antibodies have transformed the treatment of solid tumors, including colorectal cancer (CRC). In the colon, the PD-1/PD-L1 axis plays a dual and context-dependent role. During the early stages of intestinal inflammation, such as in inflammatory bowel disease (IBD), PD-1/PD-L1 signaling contributes to immune tolerance and mucosal protection. However, persistent activation of this pathway may become detrimental during the colitis-to-cancer transition, promoting immune evasion and tumor progression. Immune checkpoint inhibitors, such as nivolumab and pembrolizumab, currently approved for specific subsets of CRC, exert their effects by blocking the interaction between PD-1 and PD-L1, thereby restoring antitumor immune responses. Their use, either as monotherapy or in combination regimens, has demonstrated promising efficacy in advanced and mismatch repair-deficient CRC. This review summarizes the biphasic role of PD-1/PD-L1 in IBD and CRC, with particular emphasis on the therapeutic application of PD-1/PD-L1 blockade in CRC. It highlights monoclonal antibody-based approaches and emerging combination strategies, and finally examines current clinical trial evidence, highlighting ongoing challenges, including primary and acquired resistance to anti-PD-1/PD-L1 therapies.

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