Therapeutic targeting of PD-1/PD-L1 and CTLA-4 in colorectal cancer: tumor-intrinsic and immune checkpoint signaling

INTRODUCTION: Colorectal cancer (CRC) employs immune evasion strategies, particularly through the expression of immune checkpoint ligands, including PD-L1. These ligands interact with inhibitory receptors, including programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), which reduces the immune system's antitumor T-cell response. Modulation of these mechanisms has revolutionized the treatment paradigm, particularly for biologically distinct subsets of CRC. AREAS COVERED: This article examines the background and clinical development of immune checkpoint inhibitors (ICIs) in CRC, with particular attention to MSI-H/dMMR tumors with high mutational burden and immunogenicity. It discusses the major trials of nivolumab, pembrolizumab, and ipilimumab, including combinations from the CheckMate-142 and CheckMate-8HW trials. It also mentions new findings on tumor-intrinsic PD-1 signaling, MAPK pathway activation, and chemotherapy resistance. A thorough literature review of key trials and recent peer-reviewed publications provides a perspective on current evidence. PubMed/MEDLINE, Embase, Scopus, and the Cochrane Library (2015-2026) were searched. EXPERT OPINION: The combination of PD-1 and CTLA-4 inhibitors in MSI-H/dMMR metastatic colorectal cancer has demonstrated long-term clinical efficacy and a genuine survival benefit. However, in MSS metastatic colorectal cancer, there has been limited response, emphasizing the importance of innovative combination therapies to address both primary and secondary resistance.