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Anti-cancer effect of interleukin-2 fused to flagellin expressed by tumor-targeting Salmonella

Oncogene volume 44, pages 3449–3460 (2025)Cite this article

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Abstract

Interleukin-2 (IL2) treatment has been explored as a potent immunotherapy agent, particularly for cancers, due to its ability to stimulate T cell proliferation and activity. However, significant challenges and limitations are associated with IL2 treatment, including its short half-life, systemic toxicity and side effects, and limited efficacy in solid tumors. In this study, we deployed an attenuated Salmonella Gallinarum (SG), an avian-specific pathogen capable of targeting tumor tissue, to express and secrete the IL2 using a bacterial flagellum type 3 secretion system (T3SS). Since the T3SS is used for the secretion of flagellin monomers (FliC), DNA of the human IL2 gene was fused to the SG fliC gene so that the fusion proteins would be exported together. A superb anti-cancer effect was observed when the SG expressing and secreting the FliC-IL2 fusion protein was injected into a syngeneic tumor mouse model with CT26 colorectal cancer via the tail vein. Within the fusion protein, the FliC moiety led to a selective increase in MHCIIhighCD206- M1-like macrophages, while the IL2 moiety promoted selective expansion of cytotoxic CD8+ T cells and NK cells, without expanding CD4+FoxP3+ regulatory T cells in the tumor microenvironment (TME). It was concluded that the local delivery of IL2 within the TME by cancer-targeting SG could overcome the limitations associated with IL2-based cancer immunotherapy.

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Fig. 1: SG expressing FliC-IL2.
Fig. 2: Antitumor effects of Salmonella Gallinarum expressing FliC-IL2 in a CT26 tumor model.
Fig. 3: Immune cell profiling in the tumor microenvironment following treatment with Salmonella Gallinarum expressing FliC-IL2.
Fig. 4: Immune cell depletion reveals critical mediators of the anti-tumor effect of Salmonella Gallinarum expressing FliC-IL2.
Fig. 5: PD-1 blockade in combination with SG expressing FliC-IL2.

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Acknowledgements

This research was supported by the Bio & Medical Technology Development Program of the National Research Foundation (NRF) funded by the Korean government (MSIT) (No. NRF-2020M3A9G3080282).

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Authors and Affiliations

  1. Departments of Microbiology & Immunology, Basic Medical Research Building, Chonnam National University Medical College, Hwasun, Jeonnam, South Korea

    Thanh Quang Tran, Taner Duysak, Giang Chau Dang, Min-Hee Yi, Yoonjoo Choi, Jae Ho Cho, Jae‑Ho Jeong & Hyon E. Choy

  2. Odysseus Bio, Basic Medical Research Building, Chonnam National University Medical College, Hwasun, Jeonnam, South Korea

    Kwangsoo Kim

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Conceptualization, Hyon E. Choy and Jae-Ho Jeong; methodology, Kwangsoo Kim; data curation, Thanh Quang Tran and Taner Duysak; writing—original draft preparation, Giang Chau Dang and Thanh Quang Tran; writing—review and editing, Hyon E. Choy, Jae Ho Cho, and Yoonjoo Choi; funding acquisition, Jae-Ho Jeong. All authors have read and agreed to the published version of the manuscript. All authors read and approved of the final manuscript.

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Tran, T.Q., Duysak, T., Kim, K. et al. Anti-cancer effect of interleukin-2 fused to flagellin expressed by tumor-targeting Salmonella. Oncogene 44, 3449–3460 (2025). https://doi.org/10.1038/s41388-025-03504-y

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