A research group led by Kosuke Murakami, Lecturer in the Department of Obstetrics and Gynecology, Kindai University Faculty of Medicine (Sakai City, Osaka Prefecture), and Professor Noriomi Matsumura, Head of the Department, together with collaborators including Shiki Takamura, Team Director of the Laboratory for Immunological Memory, RIKEN Center for Integrative Medical Sciences (Wako City, Saitama Prefecture), and the Department of Immunology at Kindai University Faculty of Medicine, has revealed, through studies in both humans and mice, that a subset of clear cell ovarian cancers *2 , which has been considered difficult to treat with anticancer drugs and immunotherapy, contains a type that responds to immunotherapy. They also identified inflammation-related protein IL-17 as a key factor underlying this response. The study also discovered that IL-17 acts directly on the cancer cells and creates an immune-permissive tumor microenvironment by recruiting immune cells. Harnessing this mechanism may enable prediction of immunotherapy efficacy in individual patients, contributing to the development of personalized medicine.
The provisional version of the research article was published on June 30, 2026, and the final version was published on July 9, 2026, in Molecular Cancer , a scientific journal specializing in cancer research published by UK-based BioMed Central (BMC), Springer Nature.
Key Findings
● Discovery of an immunotherapy-responsive subtype among clear cell ovarian cancers previously considered resistant to anticancer drugs and immunotherapy in both humans and mice
● Inflammation-related protein IL-17 directly activates the cancer cells and creates an immune-permissive microenvironment by recruiting immune cells
● These findings may enable prediction of immunotherapy efficacy in individual patients, contributing to the development of personalized medicine
Background of the Study
Ovarian cancer is one of the most difficult cancers to treat among gynecological cancers. Among these, clear cell ovarian cancer accounts for about one-quarter of all ovarian cancers in Japan and is known to be more common here than in Western countries. Because clear cell ovarian cancer is resistant to anticancer drugs and remains challenging to manage after recurrence, new treatment strategies have been urgently needed.
In recent years, cancer immunotherapy (e.g., immune checkpoint inhibitors *3 ), which harnesses the body’s immune system to attack cancer, has shown promising results in the treatment of various types of cancer. However, large-scale clinical trials have not demonstrated a clear benefit in ovarian cancer. In particular, clear cell ovarian cancer has long been considered an immunologically cold tumor because it contains few surrounding immune cells. Nevertheless, previous studies have reported cases where immunotherapy was highly effective in some patients with clear cell ovarian cancer, highlighting the major challenges of understanding why only certain patients respond and how to identify those who are likely to benefit.
Overview of the Study
First, the research group analyzed tissue samples and genetic data from 180 cases of human clear cell ovarian cancer. The results revealed that, although the number of immune cells in clear cell ovarian cancer is low overall, a very small proportion (approximately 5%) exhibits a subtype in which inflammation-related protein IL-17 is highly active. This type of cancer showed an inflammatory signature, characterized by immune cell infiltration and activation within the tumor microenvironment. Crucially, this characteristic emerged independently of the markers traditionally used to predict the efficacy of immunotherapy, suggesting that IL-17 has the potential to serve as a new biomarker.
Second, we verified the mechanism by which IL-17 functions using a mouse model that replicates human clear cell ovarian cancer and cultured cells. The results revealed that IL-17 acts directly on the cancer cells themselves, triggering the inflammatory switch known as NF-κB *4 within the cells, causing them to release substances that attract and activate immune cells. When an environment conducive to IL-17 action was established in mice, increased infiltration and activation of immune cells were observed within tumors, leading to enhanced efficacy of immunotherapy (anti-PD-L1 antibody) and prolonged survival. These findings indicate that IL-17 acts as a trigger that transforms immunologically cold tumors, into a state in which the immune system can effectively attack cancer cells. Identifying tumors with high IL-17 activity may therefore provide a new biomarker for selecting patients with clear cell ovarian cancer who are likely to benefit from immunotherapy.
Publication
Journal: Molecular Cancer (Impact Factor: 42.2@2025)
Article Title: IL-17–Driven Tumor Cell–Intrinsic Inflammatory Programming Creates an Immunotherapy-Permissive Microenvironment
Authors: Kosuke Murakami 1, ＊ , Shiki Takamura 2, ＊ , Chiho Miyagawa 1 , Shiro Takamatsu 1 , Yoko Kashima 1 , Koji Nagaoka 3 , Yukari Kobayashi 3 , Yoshiyuki Hakata 4 , Shigeki Kato 3 , Sachiyo Tsuji-Kawahara 3 , Ding Nan 1 , Ronald Chandler 5 , Satoru Takahashi 6 , Masaaki Miyazawa 3 , Kazuhiro Kakimi 3 , Noriomi Matsumura 1 *Contributed equally
Affiliations: 1. Department of Obstetrics and Gynecology, Kindai University Faculty of Medicine, 2. Laboratory for Immunological Memory, RIKEN Center for Integrative Medical Sciences, 3. Department of Immunology, Kindai University Faculty of Medicine, 4. Department of Arts and Sciences, Kindai University Faculty of Medicine, 5. Department of Obstetrics, Gynecology and Reproductive Biology, College of Human Medicine, Michigan State University, 6. Department of Anatomy and Embryology and Laboratory Animal Resource Center in Transborder Medical Research Center, Institute of Medicine, University of Tsukuba,
URL: https://link.springer.com/article/10.1186/s12943-026-02726-2
DOI: https://doi.org/10.1186/s12943-026-02726-2
Details of the Study
Ovarian clear cell carcinoma is characterized by a slightly higher number of CD4-positive T cells *5 , a feature that caught the research group’s attention. Analysis of large-scale genomic datasets revealed that a subset of cancers with high IL-17 activity develop an inflammatory state characterized by the recruitment and activation of immune cells. This state emerged independently of conventional biomarkers for predicting treatment response, such as microsatellite instability (MSI ※ 6 ) and high tumor mutational burden (TMB ※ 6 ).
Furthermore, the study confirmed that IL-17 acts directly on cancer cells without involving immune cells to activate NF-κB, thereby inducing the production of substances such as chemokines that recruit immune cells. In mouse models, tumors exposed to IL-17 showed increased recruitment and activation of immune cells within the tumor microenvironment. Additionally, single-cell-level analysis revealed that these immune cells were not dysfunctional but retained their ability to attack the tumor. Furthermore, mice with an inflammatory tumor microenvironment showed prolonged survival following treatment with an anti–PD-L1 antibody, whereas no survival difference was observed in the absence of immunotherapy. These results indicate that IL-17 is not a marker of prognosis, but rather a biomarker for predicting the response to immunotherapy.
These findings present new insights that may apply not only to clear cell ovarian cancer but also to a wide range of cancer types, suggesting that the inflammatory environment created by the cancer cells themselves influences the efficacy of immunotherapy.
Researcher Comment ary
Kosuke Murakami
Affiliation: Department of Obstetrics and Gynecology, Kindai University Faculty of Medicine
Position: Lecturer, Faculty of Medicine
Degree: Doctor of Medicine
Comment: Clear cell ovarian cancer is resistant to anticancer drugs, and immunotherapy has not been accessible to many patients.
Although it represents only a small subset, we have demonstrated that there are indeed cancer types that are highly responsive to immunotherapy, and that inflammation induced by IL-17 is the key factor underlying this response. This achievement was made possible only through close collaboration between RIKEN and the Faculty of Medicine at our university. We hope to further advance our research toward the realization of personalized medicine by identifying patients who are likely to benefit from treatment and delivering the optimal therapy for each individual.
[Glossary]
*1 IL-17: Interleukin-17. A type of protein (cytokine) involved in inflammation, produced by immune cells and other cells.
*2 Clear cell ovarian cancer: A histological subtype of ovarian cancer. It accounts for approximately one-quarter of ovarian cancer cases in Japanese women and is known for being difficult to treat due to its resistance to anticancer drugs.
*3 Immune checkpoint inhibitors: Drugs that release the “brakes” placed on the immune system by cancer cells, allowing the immune system to attack cancer. Representative examples include anti-PD-1 antibodies and anti-PD-L1 antibodies.
*4 NF-κB: A protein that acts as a command center within cells, simultaneously regulating the activity of many genes involved in inflammation and immunity.
*5 CD4-positive T cells: T cells are central immune cells that attack foreign substances and cancer cells that have invaded the body; they are broadly classified into CD4-positive T cells and CD8-positive T cells.
*6 MSI and TMB: These stand for microsatellite instability and tumor mutational burden, respectively. These are markers that have been used to predict the likelihood of a response to immunotherapy.
Molecular Cancer
Experimental study
People
IL-17–Driven Tumor Cell–Intrinsic Inflammatory Programming Creates an Immunotherapy-Permissive Microenvironment
30-Jun-2026
Kosuke Murakami received a research grant from Eisai. Noriomi Matsumura received lecture fees from Chugai Pharmaceutical, AstraZeneca, and Takeda Pharmaceutical, as well as a research grant from AstraZeneca. Noriomi Matsumura is also an outside director of Takara Bio. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.