Immune checkpoint inhibitors have revolutionized cancer treatment, yet many colorectal tumors remain resistant. Even among patients who initially respond, more than half eventually develop resistance, highlighting the need to better understand how tumors evade immune attack. Although chronic inflammation has long been linked to epigenetic changes in cancer, exactly how inflammatory signals reprogram the cancer-cell epigenome and reshape the tumor microenvironment has remained unclear. Emerging evidence has implicated the inflammatory cytokine interleukin (IL)-26 in tumor-associated inflammation, but its role in driving immune escape and resistance to anti-programmed death protein 1 (PD-1) immunotherapy remained unknown.
In a groundbreaking study published in the journal of Nature Communications on July 17, 2026, 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, along with colleagues, investigated how IL-26-producing type 17 T cells contribute to immune checkpoint inhibitor resistance in colorectal cancer. The team sought to uncover the molecular mechanism by which the immune-derived cytokine IL-26 reprograms tumor cells to evade immune attack. "We identified the immune-derived cytokine IL-26 as an unusual regulator that acts directly on cancer cells, triggering epigenetic reprogramming and reshaping the tumor microenvironment to promote immune escape," says Dr. Itoh.
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 tumor biology from the molecular to the whole-organism level.
The study revealed that IL-26-producing CD8⁺ type 17 T cells accumulated in anti-PD-1-resistant colorectal tumors. Unlike conventional cytokines, IL-26 entered tumor cell nuclei, where it interacted with STAT1 and recruited transcriptional regulators, including nuclear factor kappa B and BRD4. This activated an epigenetic program that increased CXCL1, CXCL2, CXCL3, and CXCL7 expression, attracting immunosuppressive neutrophils. These neutrophils weakened antitumor 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 antitumor immunity and improved immunotherapy responses in preclinical models.
Together, these findings reveal that IL-26 fundamentally reshapes the tumor immune landscape by linking inflammation to epigenetic remodeling and immune suppression. Explaining the biological impact of the findings, Dr. Itoh notes, "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 tumor microenvironment, creating inflammatory conditions that promote immune evasion and tumor progression." Together, the findings identify the IL-26–STAT1–BRD4 axis as a previously unrecognized mechanism linking inflammation, epigenetic remodeling, and immunotherapy resistance, offering a promising target for improving colorectal cancer treatment.
Beyond identifying a new mechanism of immune escape, the findings open new opportunities for overcoming resistance to immune checkpoint blockade. Therapeutic strategies targeting IL-26 or disrupting its downstream epigenetic program could complement existing anti-PD-1 therapies by preventing neutrophil-driven immune suppression and restoring effective antitumor immune responses. "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," says Dr. Itoh.
Overall, this study reveals IL-26 as a critical link between immune-cell signaling, epigenetic reprogramming, and tumor immune evasion. By uncovering how an inflammatory cytokine can transform cancer cells into a more immunosuppressive state, the research identifies a promising therapeutic vulnerability and provides a foundation for developing next-generation combination therapies to improve cancer immunotherapy outcomes.
Reference
Authors: Takumi Itoh1, Ryo Hatano1, Yuta Hasegawa1, Nao Hosokawa1, Kazuyoshi Takeda2, 3, 4, Ayako Yamamoto1, Yoshiya Horimoto5, 6, 7, Jinghui Yu 1, Hayato Nakamura1, Harumi Saeki5, Shogo Ehata8, Shuji Matsuoka9, Haruna Otsuka1, Hiroshi Ohtsu10, Michio Tomura11, Nam H. Dang12, Yutaro Kaneko13, Kei Ohnuma1, and Chikao Morimoto1
Title of original paper: IL-26-driven epigenetic remodeling promotes immune evasion in colorectal cancer
Journal: Nature Communications
DOI: https://doi.org/10.1038/s41467-026-75754-7
Affiliations:
¹Department of Therapy Development and Innovation for Immune Disorders and Cancers, Graduate School of Medicine, Juntendo University, Japan
²Laboratory of Cell Biology, Research Support Center, Graduate School of Medicine, Juntendo University, Japan
³Center for Immune Therapeutics and Diagnosis, Graduate School of Medicine, Juntendo University, Japan
⁴Department of Biofunctional Microbiota, Graduate School of Medicine, Juntendo University, Japan
⁵Department of Human Pathology, Juntendo University School of Medicine, Japan
⁶Department of Breast Oncology, Juntendo University School of Medicine, Japan
⁷Department of Breast Surgery and Oncology, Tokyo Medical University, Japan
⁸Department of Pathology, School of Medicine, Wakayama Medical University, Japan
⁹Department of Immunological Diagnosis, Graduate School of Medicine, Juntendo University, Japan
¹⁰Faculty of Health Data Science, Juntendo University, Japan
¹¹Laboratory of Immunology, Faculty of Pharmacy, Osaka Ohtani University, Japan
¹²Division of Hematology/Oncology, University of Florida, U.S.A.
¹³Y's AC Co., Ltd., Japan
About Assistant Professor Takumi Itoh
Dr. Takumi Itoh is an Assistant Professor at the Department of Therapy Development and Innovation for Immune Disorders and Cancers, Juntendo University, Japan. His research focuses on immunology, cytokine functions, and epigenetic mechanisms in chronic inflammatory diseases and cancer.
History of Juntendo University
Juntendo was originally founded in 1838 as a Dutch School of Medicine at a time when Western medical education was not yet embedded as a normal part of Japanese society. With the creation of Juntendo, the founders hoped to create a place where people could come together with the shared goal of helping society through the powers of medical education and practices. Their aspirations led to the establishment of Juntendo Hospital, the first private hospital in Japan. Through the years the institution's experience and perspective as an institution of higher education and a place of clinical practice has enabled Juntendo University to play an integral role in the shaping of Japanese medical education and practices. Along the way the focus of the institution has also expanded, now consisting of nine undergraduate programs and six graduate programs, the university specializes in the fields of health science, health and sports science, nursing health care and sciences, and international liberal arts, as well as medicine. Today, Juntendo University continues to pursue innovative approaches to international level education and research with the goal of applying the results to society.
Mission Statement
The mission of Juntendo University is to strive for advances in society through education, research, and healthcare, guided by the motto "Jin – I exist as you exist" and the principle of "Fudan Zenshin - Continuously Moving Forward". The spirit of "Jin", which is the ideal of all those who gather at Juntendo University, entails being kind and considerate of others. The principle of "Fudan Zenshin" conveys the belief of the founders that education and research activities will only flourish in an environment of free competition. Our academic environment enables us to educate outstanding students to become healthcare professionals patients can believe in, scientists capable of innovative discoveries and inventions, and global citizens ready to serve society.
