Researchers have identified inflammatory cytokine interleukin-26 (IL-26) as a factor that acts on cancer cells and induces epigenetic reprogramming, promoting immune evasion. 

While cancer cells acquire malignant traits through epigenetic remodelling, it remains unclear how immune-derived inflammatory factors regulate the epigenetics of colorectal cancer cells.  

Now, researchers have discovered that the IL-26 produced by exhausted T cells can reprogramme the cancer cell epigenome, promoting immune evasion. 

The findings provide new insights into the complex landscape of cancer immunotherapy and highlight potential opportunities to improve future treatment strategies. 

Immune checkpoint inhibitors have revolutionised cancer treatment, yet many colorectal tumours remain resistant. Even among patients who initially respond, more than half eventually develop resistance. 

Although chronic inflammation has long been linked to epigenetic changes in cancer, exactly how inflammatory signals reprogramme the cancer-cell epigenome and reshape the tumour microenvironment has remained unclear. 

In a new study, a team of researchers led by Assistant Professor Takumi Itoh from the Department of Therapy Development and Innovation for Immune Disorders and Cancers, Graduate School of Medicine, Juntendo University, Japan, investigated how IL-26-producing type 17 T cells contribute to immune checkpoint inhibitor resistance in colorectal cancer. 

To uncover this mechanism, the researchers combined single-cell RNA sequencing and transcriptomic analyses of human colorectal cancer samples with human IL-26 transgenic and inflammation-induced mouse models.  

They complemented these studies with a series of cellular and molecular experiments, including immunofluorescence, chromatin immunoprecipitation sequencing, co-immunoprecipitation, and targeted inhibition of IL-26, signal transducer and activator of transcription 1 (STAT1), bromodomain-containing protein 4 (BRD4), C-X-C motif chemokine ligand (CXCL), and neutrophils, enabling them to trace how IL-26 influences tumour biology from the molecular to the whole-organism level. 

Reshaping the tumour immune landscape 

The study revealed that IL-26-producing CD8⁺ type 17 T cells accumulated in anti-PD-1- resistant colorectal tumours. Unlike conventional cytokines, IL-26 entered tumour cell nuclei, where it interacted with STAT1 and recruited transcriptional regulators, including nuclear factor kappa B and BRD4. This activated an epigenetic programme that increased CXCL1, CXCL2, CXCL3, and CXCL7 expression, attracting immunosuppressive neutrophils. These neutrophils weakened antitumour CD8⁺ T-cell activity, enabling immune evasion and reducing the effectiveness of anti-PD-1 therapy. Importantly, targeting IL-26, BRD4, CXC receptor 2, or neutrophils restored antitumour immunity and improved immunotherapy responses in preclinical models. 

Together, these findings reveal that IL-26 fundamentally reshapes the tumour immune landscape by linking inflammation to epigenetic remodelling and immune suppression. 

Dr Itoh noted: “We identified IL-26 as a rare cytokine capable of inducing epigenetic changes in cancer cells. IL-26 increased the expression of CXCL chemokines by several thousand-fold. This effect was sufficiently powerful to substantially reshape the tumour microenvironment, creating inflammatory conditions that promote immune evasion and tumour progression. 

“In the future, developing therapeutic strategies blocking IL-26 or preventing the epigenetic changes could potentially improve the effectiveness of immunotherapy in treatment-resistant cancers, leading to new treatments for a wide range of cancers and chronic inflammatory diseases.”