Colorectal cancer may resist immunotherapy not only because tumor cells acquire genetic changes, but also because inflammatory signals can reprogram their epigenetic state, according to a new study from researchers at Juntendo University in Japan. The work identifies interleukin-26, or IL-26, as a central driver of this process. The cytokine appears to enter colorectal cancer cells, alter the way their DNA is regulated, and stimulate the production of chemical signals that attract immune-suppressive neutrophils. By creating a tumor environment hostile to immune attack, this IL-26-driven pathway can weaken the effects of anti-programmed death protein 1, or anti-PD-1, therapy.
Immune checkpoint inhibitors have transformed treatment for several advanced cancers by releasing molecular brakes that prevent T cells from attacking malignant cells. Anti-PD-1 drugs work by blocking the interaction between PD-1 on T cells and its ligands on tumor or immune cells, allowing exhausted T cells to regain some of their cytotoxic activity. However, colorectal cancer remains a particularly difficult setting for immunotherapy. Only a subset of tumors responds effectively, and many patients who initially benefit eventually develop acquired resistance. The new findings suggest that chronic inflammation may help explain why this resistance develops, by changing not only the immune cells surrounding a tumor but also the internal regulatory machinery of the cancer cells themselves.
The study, published in Nature Communications, was led by Assistant Professor Takumi Itoh of the Department of Therapy Development and Innovation for Immune Disorders and Cancers at Juntendo University’s Graduate School of Medicine. The researchers examined human colorectal cancer samples using single-cell RNA sequencing and broader transcriptomic analyses, then tested their observations in human IL-26 transgenic mice and inflammation-induced mouse models. These approaches were combined with immunofluorescence imaging, chromatin immunoprecipitation sequencing, co-immunoprecipitation experiments, and targeted interventions directed against IL-26, STAT1, BRD4, CXCL chemokines, the chemokine receptor CXCR2, and neutrophils. Together, the experiments followed the mechanism from cytokine production by immune cells to epigenetic changes inside tumor cells and, ultimately, altered responses to immunotherapy.
The researchers found that IL-26-producing CD8-positive type 17 T cells accumulated in colorectal tumors that had become resistant to anti-PD-1 treatment. Type 17 T cells are associated with inflammatory immune responses and can produce cytokines that influence both neighboring immune cells and tissue cells. In this case, IL-26 behaved in an unusual way. Rather than acting solely through receptors at the cell surface, the cytokine was detected inside the nuclei of tumor cells. There, it interacted with signal transducer and activator of transcription 1, known as STAT1, a transcriptional regulator that can move into the nucleus after cytokine signaling and bind regulatory regions of DNA. The findings indicate that IL-26 helped assemble a transcriptional complex involving STAT1, nuclear factor kappa B, and bromodomain-containing protein 4, or BRD4.
BRD4 is an epigenetic reader: it recognizes acetylated histones, the proteins around which DNA is wrapped, and helps recruit machinery that activates gene transcription. By engaging BRD4, inflammatory signaling can produce changes in gene activity without changing the DNA sequence itself. The Juntendo team’s experiments showed that the IL-26–STAT1 interaction promoted BRD4-associated regulatory activity at regions controlling genes for several C-X-C motif chemokines, including CXCL1, CXCL2, CXCL3, and CXCL7. These molecules are powerful chemoattractants. Their expression increased by several thousand-fold in some experimental settings, indicating that the pathway could convert a relatively localized inflammatory signal into a large-scale remodeling of the tumor microenvironment.
The consequences were particularly significant for neutrophils. Chemokines such as CXCL1 and CXCL2 can recruit neutrophils through CXCR2, a receptor expressed on these cells. Although neutrophils are essential components of normal host defense, tumors can manipulate them into immunosuppressive states. Within the colorectal tumor models examined in the study, the influx of neutrophils was associated with weakened antitumor CD8-positive T-cell activity. These neutrophils helped create conditions in which cancer-directed T cells were less effective, even when PD-1 signaling was pharmacologically blocked. The result was a feedback loop in which inflammation promoted chemokine production, chemokines recruited suppressive neutrophils, and the altered immune environment allowed the tumor to evade immune destruction.
The researchers then tested whether disrupting different components of this pathway could restore treatment sensitivity. Blocking IL-26 reduced the inflammatory program in tumor cells. Inhibiting BRD4 interfered with the epigenetic machinery responsible for maintaining increased chemokine transcription. Targeting CXCR2 limited neutrophil recruitment, while direct depletion or inhibition of neutrophils reduced their suppressive influence within the tumor. In preclinical models, these interventions improved antitumor immune responses and enhanced the activity of anti-PD-1 therapy. The results point to the IL-26–STAT1–BRD4 axis as a possible therapeutic vulnerability, although the experiments do not yet establish that the approach is safe or effective in human patients.
The findings also broaden the understanding of how inflammatory cytokines can influence cancer biology. Cytokines are often described as soluble messengers that bind receptors and activate signaling cascades, but IL-26 appears capable of exerting a more direct influence on the tumor-cell nucleus. By coupling immune-derived signaling to epigenetic regulation, it may give cancer cells the ability to reshape the immune landscape around them. Dr. Itoh described IL-26 as a rare cytokine capable of inducing epigenetic changes in cancer cells and emphasized that the resulting increase in CXCL chemokines was strong enough to substantially alter the tumor microenvironment. This mechanism offers a molecular explanation for how chronic inflammation can become an active participant in immunotherapy resistance rather than merely a background feature of the disease.
The study raises the possibility of combining anti-PD-1 drugs with therapies directed against IL-26, BRD4, CXCR2, or neutrophil-mediated suppression. Such combinations could be especially relevant for patients whose tumors contain high levels of IL-26-producing type 17 T cells or show evidence of CXCL-driven neutrophil infiltration. Before clinical applications can be considered, researchers will need to determine how common this pathway is across colorectal cancer subtypes and other malignancies, whether IL-26 activity can be measured reliably in patients, and how broadly its blockade can be applied without disrupting protective immune functions. The study also includes potential conflicts of interest: several researchers are inventors and patent holders of a humanized anti-IL-26 antibody, while some authors hold relationships with a company connected to the technology. Even with these considerations, the work provides a detailed preclinical framework for understanding how inflammation, epigenetic remodeling, and immune escape can converge to undermine cancer immunotherapy.
By revealing that IL-26 can drive a STAT1- and BRD4-dependent transcriptional program in colorectal cancer cells, the researchers have identified a previously unrecognized connection between immune signaling and cancer-cell epigenetics. The pathway does not simply suppress T cells directly; it changes the tumor’s chemical environment, recruits neutrophils, and helps establish resistance to immune checkpoint blockade. If future studies confirm the mechanism in patients, blocking IL-26-driven reprogramming could become part of a new generation of combination strategies designed to make resistant tumors visible and vulnerable to the immune system again.
Subject of Research: Animals
Article Title: IL-26-driven epigenetic remodeling promotes immune evasion in colorectal cancer
Web References: https://doi.org/10.1038/s41467-026-75754-7
References: Takumi Itoh, Ryo Hatano, Yuta Hasegawa, Nao Hosokawa, Kazuyoshi Takeda, Ayako Yamamoto, Yoshiya Horimoto, Jinghui Yu, Hayato Nakamura, Harumi Saeki, Shogo Ehata, Shuji Matsuoka, Haruna Otsuka, Hiroshi Ohtsu, Michio Tomura, Nam H. Dang, Yutaro Kaneko, Kei Ohnuma, and Chikao Morimoto. “IL-26-driven epigenetic remodeling promotes immune evasion in colorectal cancer.” Nature Communications. DOI: 10.1038/s41467-026-75754-7
Image Credits: Dr. Takumi Itoh, Juntendo University, Japan
Keywords: IL-26, colorectal cancer, cancer immunology, immunotherapy resistance, anti-PD-1 therapy, epigenetic remodeling, STAT1, BRD4, CXCL chemokines, neutrophils, tumor microenvironment, cancer research
