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Translational Therapeutics

IL-33 released during liver resection facilitates intrahepatic cholangiocarcinoma growth via cytokine secretion in cancer-associated fibroblasts

British Journal of Cancer volume 134, pages 519–529 (2026)Cite this article

Subjects

Abstract

Background

We previously reported that IL-33 released during hepatectomy contributes to cytokine-facilitated iCCA tumor growth. However, the underlying mechanisms of the tumor microenvironment remain unexplored. In this study, we aimed to elucidate the impact of IL-33 on cancer-associated fibroblasts (CAFs).

Methods

The abundance of IL-33-positive cells and alpha-SMA-positive fibroblasts (myoCAFs) was evaluated using resected specimens. Next-generation sequencing (NGS) was performed for comprehensive expression analysis. The effects of IL-33 stimulation on CAFs were investigated in vitro and in vivo using human and murine iCCA cell lines, as well as fibroblasts extracted from resected specimens.

Results

IL-33-positive cells and myoCAFs were significant risk factors for intrahepatic recurrence. NGS analysis revealed significant upregulation of various cytokines in cases with high number of IL-33-positive cells. The conditioned medium obtained from fibroblasts stimulated with IL-33 enhanced the proliferation and migration of iCCA cell lines. Among the cytokines that were increased by IL-33 stimulation in vitro, IL-6 was suspected to be the dominant. In a murine syngraft model, hepatectomy led to an increased subcutaneous tumor volume by releasing IL-33, whereas IL-6 blockade suppressed this growth.

Conclusions

This study indicated that IL-33 facilitates iCCA growth through fibroblast activation and is associated with intrahepatic recurrence.

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Fig. 1: Clinical significance of myoCAFs and IL-33 in iCCA.
Fig. 2: Next-generation sequencing detecting of upregulated mRNA expression in IL-33 high expression in iCCA tissue (n = 4).
Fig. 3: Comparison of malignant potency among three groups.
Fig. 4: Identification of cytokines whose release from CAFs was increased by IL-33 stimulation and the influence on the iCCA cell line.
Fig. 5: Effect of CAFs and IL-6 on tumorigenesis in vivo.

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Data availability

The data that support the findings of this study are available from the corresponding author, [S.K.], upon reasonable request. Individual participant data will not be available.

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Acknowledgements

We would like to thank Editage (www.editage.jp) for English language editing.

Funding

Grant-in-Aid for Scientific Research (C), The Ministry of Education, Culture, Sports, Science and Technology (MEXT).

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Authors and Affiliations

  1. The Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, Suita, Japan

    Satoshi Eguchi, Daisaku Yamada, Shogo Kobayashi, Kazuki Sasaki, Yoshifumi Iwagami, Chihiro Yamanaka, Yoshito Tomimaru, Takehiro Noda, Masaki Sakaue, Tadafumi Asaoka, Junzo Shimizu, Hidenori Takahashi, Yuichiro Doki & Hidetoshi Eguchi

  2. The Department of Gastroenterological Surgery, Japan Community Health care Organization Osaka Hospital, Osaka, Japan

    Chihiro Yamanaka

  3. The Department of Gastroenterological Surgery, Osaka Police Hospital, Osaka, Japan

    Tadafumi Asaoka

  4. The Department of Gastroenterological Surgery, Toyonaka Municipal Hospital, Osaka, Japan

    Junzo Shimizu

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Contributions

S.E.: conception and design, acquisition of data, and analysis and interpretation of data; drafted the manuscript; and approved the final version for publication. D.Y.: conception and design, acquisition of data, and analysis and interpretation of data; revised the manuscript critically for important intellectual content; and approved the final version for publication. S.K.: conception and design, acquisition of data, and analysis and interpretation of data; revised the manuscript critically for important intellectual content; and approved the final version for publication. K.S.: conception, design, and acquisition of data; revised the manuscript critically for important intellectual content; and approved the final version for publication. Y.I.: conception, design, and acquisition of data; revised the manuscript critically for important intellectual content; and approved the final version for publication. C.Y: conception, design, and acquisition of data; revised the manuscript critically for important intellectual content; and approved the final version for publication. Y.T: conception, design, and acquisition of data; revised the manuscript critically for important intellectual content; and approved the final version for publication. T.N.: conception and design, acquisition of data, and analysis and interpretation of data; revised the manuscript critically for important intellectual content; and approved the final version for publication. M.S.: conception and design, acquisition of data, and analysis and interpretation of data; revised the manuscript critically for important intellectual content; and approved the final version for publication. T.A.: conception and design, acquisition of data, and analysis and interpretation of data; revised the manuscript critically for important intellectual content; and approved the final version for publication. M.T.: conception and design, acquisition of data, and analysis and interpretation of data; revised the manuscript critically for important intellectual content; and approved the final version for publication. H.T.: conception and design, acquisition of data, and analysis and interpretation of data; revised the manuscript critically for important intellectual content; and approved the final version for publication. Y.D: conception and design, acquisition of data, and analysis and interpretation of data; revised the manuscript critically for important intellectual content; and approved the final version for publication. H.E.: conception and design and analysis and interpretation of the data; revised the manuscript critically for important intellectual content; and approved the final version for publication.

Corresponding author

Correspondence to Shogo Kobayashi.

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Competing interests

S.K. has received honoraria from AstraZeneca, Novartis, Olympus, and Taiho. All other authors declare no competing interests.

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Eguchi, S., Yamada, D., Kobayashi, S. et al. IL-33 released during liver resection facilitates intrahepatic cholangiocarcinoma growth via cytokine secretion in cancer-associated fibroblasts. Br J Cancer 134, 519–529 (2026). https://doi.org/10.1038/s41416-025-03256-2

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