Dayla Trillayes

Background: Lynch syndrome is the most common hereditary colorectal cancer syndrome and results from germline mutations in DNA mismatch repair (MMR) genes, including MLH1 and MSH2.² Defective MMR causes microsatellite instability and accumulation of replication errors, producing a high mutational burden and neoantigens that stimulate immune recognition by CD8+ T cells.¹,² Despite this immunogenic environment, tumor progression still occurs, indicating the presence of immune-evasion mechanisms. Recent evidence identifies enhancer of zeste homolog 2 (EZH2), the catalytic component of the polycomb repressive complex 2 (PRC2), as a key epigenetic regulator that promotes transcriptional repression through trimethylation of histone H3 lysine 27 (H3K27me3).¹ EZH2-mediated silencing of tumor suppressor and immune-response genes may permit early neoplastic lesions to evade immune surveillance and progress toward colorectal carcinoma.¹

Objective: In this literature review, I evaluated the role of EZH2-mediated epigenetic regulation in immune suppression and assessed whether pharmacologic EZH2 inhibition can restore antitumor immunity and prevent colorectal cancer progression in Lynch syndrome.

Search Methods: A narrative literature review was conducted using PubMed and related biomedical literature. Search terms included “Lynch syndrome,” “colorectal cancer,” “EZH2,” “epigenetic regulation,” and “immune interception.” Literature published from 2021–2026 was reviewed, with emphasis placed on the primary investigation by Bowen et al.

Results: Lynch syndrome-associated tumors demonstrate abundant neoantigen formation and immune-cell infiltration due to their elevated mutation burden.¹ However, EZH2 suppresses immune-response genes, limiting immune activation and promoting tumor survival.¹ In a conditional Msh2-deficient Lynch syndrome mouse model, Bowen et al. demonstrated that treatment with the EZH2 inhibitor GSK503 significantly reduced colorectal tumor burden and lesion number by approximately 40–50% compared with controls.¹ At baseline, both the control group and treated group started with a similar number of polyps, about 5. However, over time, the control group continues to develop more polyps, while the treated group shows a reduction in polyp numbers. By around 6 weeks, there was a significant difference in polyps between both groups, with the control group at about 7 polyps and the treated GSK503 group at about 3 polyps. When we look specifically at the large intestine polyps found during the necropsy, we see a statistically significant reduction in polyp count in the treated group (2) compared to control (4-5). There was not a significant difference between groups for small intestine polyps, showing that GSK503 is colon specific.¹ In addition to this reduction in polyps, the treated group exhibited increased infiltration of CD8+ T cells, activated CD8+ T cells, CD4+ T cells, and CD335+ natural killer cells, indicating restoration of immune surveillance.¹ Western blot and chromatin immunoprecipitation sequencing analyses confirmed decreased H3K27me3 methylation following treatment, while single-cell RNA sequencing demonstrated expansion of immune-cell populations within intestinal tissues.¹ Furthermore, demethylation and reactivation of tumor suppressor genes, including Nptx1, supported a mechanistic link between EZH2 inhibition and suppression of neoplastic progression.¹

Conclusion: EZH2 functions as a critical mediator of immune evasion in Lynch syndrome associated colorectal tumorigenesis by epigenetically silencing immune response and tumor suppressor genes.¹ Pharmacologic inhibition of EZH2 restores immune-cell activity, reverses repressive methylation patterns, and significantly decreases tumor burden in preclinical models.¹ These findings support EZH2 inhibition as a promising immune interception strategy for hereditary colorectal cancer prevention. Future clinical studies are needed to determine the long-term efficacy, safety, and translational potential of EZH2-targeted therapies in high-risk patient populations.

Works Cited

1. Bowen CM, Duzagac F, Martel-Martel A, et al. Inhibition of histone methyltransferase EZH2 for immune interception of colorectal cancer in Lynch syndrome. JCI Insight. 2025;10(6):e177545. doi:10.1172/jci.insight.177545
2. MedlinePlus. Lynch syndrome. U.S. National Library of Medicine. Updated April 15, 2021. Accessed April 21, 2026. https://medlineplus.gov/genetics/condition/lynch-syndrome/
3. BioRender. Antigen presentation in cancer. BioRender. Accessed April 21, 2026. https://app.biorender.com/biorender-templates/details/t-60807f3997974400aba838df-antigen-presentation-in-cancer/