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  • Immune Checkpoints Dysregulation in Precancerous Colorectal Polyps

  • Mahtab Gharibi ,1 Marziyeh Etesami,2,*
    1. Department of Genetics, TeMS.C., Islamic Azad University,Tehran, Iran.
    2. Department of Genetics and Biotechnology, VaP.C, Islamic Azad University, Varamin, Iran.


  • Introduction: Colorectal cancer (CRC) is one of the most common cancers and a leading cause of cancer-related mortality worldwide. Colorectal cancer develops through a multistep process in which progressive genetic, epigenetic, and immunological changes contribute to malignant transformation. Increasing evidence suggests that immune dysregulation begins during the premalignant stages of colorectal tumorigenesis. Immune checkpoints play important roles in regulating immune responses. Alterations in the expression and activity of immune checkpoint molecules have been reported in precancerous colorectal polyps and colorectal cancer and have been associated with lesion progression and clinical outcomes. Therefore, the aim of this narrative review is to investigate the dysregulation of immune checkpoints in precancerous colorectal polyps and their relationship with lesion progression and clinical outcomes.
  • Methods: The sources for this narrative review were collected through searches of Google Scholar and PubMed. Full-text articles and published abstracts from 2021 to 2026 were reviewed. The reviewed studies included both peripheral blood and tissue specimens from patients with colorectal precancerous polyps and colorectal cancer.
  • Results: Recent studies have shown that significant immune changes can be detected as early as the development of colorectal polyps in patients. In-depth phenotyping of the peripheral blood immune system has revealed changes in several T-cell populations in individuals with non-advanced and advanced colorectal polyps. In terms of immune exhaustion, three checkpoints, programmed cell death protein 1 (PD-1), V-domain Ig suppressor of T-cell activation (VISTA), and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), were examined, but the pattern of their changes was not uniform; PD-1 was increased in some subpopulations and decreased in others, while CTLA-4 showed the greatest difference between groups. Another study also showed increased expression of CTLA-4 in adenomatous and hyperplastic polyps, suggesting that systemic immune changes occur before the development of invasive CRC. In contrast, increased CTLA-4 expression in tumor epithelial cells was associated with dysplastic adenomas and CRC, whereas its expression in tumor-infiltrating lymphocytes was associated with a better prognosis. Therefore, the location of immune checkpoint molecule expression may influence their clinical significance. The cyclooxygenase-2–prostaglandin E2–prostaglandin E2 receptor 4 (COX-2–PGE2–EP4) pathway appears to contribute to an immunosuppressive environment by increasing PD-1 expression during colorectal adenoma formation and growth. This suggests that inflammatory mediators can directly affect immune checkpoint-related pathways. Transcriptomic analyses have also identified distinct immune phenotypes among colorectal adenomas. Activation of the T-cell immunoreceptor with Ig and ITIM domains (TIGIT) pathway and exhaustion of CD8+ T cells were detected at the adenoma stage and increased during progression to CRC. These observations suggest that immune exhaustion is not simply a consequence of advanced cancer but may also occur during premalignant transformation. Another study examined inducible T-cell co-stimulator (ICOS) and ICOS ligand (ICOSLG) and showed increased expression of these molecules from hyperplastic and dysplastic polyps to high-grade dysplasia and CRC. The ICOS/ICOSLG axis, as a T-cell co-stimulatory pathway, increased along with PD-1 during adenoma-to-carcinoma progression and was associated with the formation of an immunosuppressive environment in more advanced stages. Finally, a recent study showed that adenoma-to-carcinoma progression is associated with an increase in exhausted CD8+ T cells (CD8 Tex) and increased expression of immune checkpoints such as PD-1, lymphocyte activation gene 3 (LAG3), and T-cell immunoglobulin and mucin-domain containing 3 (TIM3). Functional experiments showed that CD8 Tex may induce the expression of runt-related transcription factor 2 (RUNX2) in adenomas and play a role in adenoma-to-carcinoma progression.
  • Conclusion: Collectively, the available evidence suggests that dysregulation of immune checkpoints is an early and progressive event during colorectal tumorigenesis. Understanding the dynamic regulation of these pathways throughout the adenoma–carcinoma sequence could help to better identify early biomarkers and provide a stronger biological basis for the development of immune-based therapeutic strategies in CRC. Future studies should move beyond the evaluation of individual immune checkpoints and instead examine the interplay between multiple immune checkpoint pathways, immune cell populations, and inflammatory signals during the adenoma–carcinoma sequence.
  • Keywords: Colorectal polyps; Colorectal cancer; Immune Checkpoints; Immune dysregulation

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