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TNFSF15 alleviates myeloid-derived suppressor cell-mediated cancer immunosuppression in mice

Acta Pharmacologica Sinica volume 47, pages 493–503 (2026)Cite this article

Abstract

Myeloid-derived suppressor cells (MDSCs) are a category of immature myeloid cells that have an important function in suppressing immune responses in a variety of pathological settings. Thus, MDSCs are the subject of intensive studies regarding their recruitment, expulsion, deactivation, and maturation promotion. Tumor necrosis factor superfamily member 15 (TNFSF15) is produced largely by vascular endothelial cells in mature blood vessels with expression also observed in tumor-associated macrophages (TAMs) and dendritic cells (DCs) within the tumor stroma. In addition to inhibiting the proliferation of vascular endothelial cells and the differentiation of bone marrow-derived endothelial cell progenitors, TNFSF15 is able to promote the maturation of DC, as well as to modulate the polarization of naive M2-macrophages into M1-macrophages capable of eliminating cancer cells, and activate T-cell. In this study, we investigated whether a recombinant TNFSF15 results in a substantial reduction of MDSC accumulation in Lewis lung cancer (LLC) tumor-bearing mice. LLC allograft model mice were administered recombinant TNFSF15 (5 mg·kg−1·d−1, i.p.) for 7 consecutive days. The tumor, bone marrow and spleen were retrieved on Day 8 and analyzed using flow cytometry or immunofluorescence staining. We showed that TNFSF15 treatment significantly inhibited the tumor growth, and caused a substantial reduction of MDSC accumulation in the tumors. The proportions of MDSC in the bone marrows and the spleens were also reduced. The diminished MDSC was mainly the monocyte-like MDSC (M-MDSC) subtype. Additionally, the reduction in M-MDSC population was accompanied by an increase of the proportions of macrophages and DCs in the tumors. We demonstrated that TNFSF15 promoted M-MDSC differentiation by activating the JAK1/STAT3 signaling pathway. Moreover, the treatment gave rise to a markedly escalated accumulation of cytotoxic T cells in the tumors, attributing to tumor growth inhibition. Our results support the view that TNFSF15-driven differentiation of M-MDSC into DCs and macrophages, and the subsequent activation of T cells, may contribute partially to reinstitution of immunity in the tumor microenvironment.

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Fig. 1: TNFSF15 inhibits the accumulation of MDSCs in tumor-bearing mice.
Fig. 2: TNFSF15 inhibits the accumulation of M-MDSCs and the function of MDSC in tumor-bearing mice.
Fig. 3: TNFSF15 regulates MDSCs and macrophage/DC balance in the tumor microenvironment.
Fig. 4: TNFSF15 restores MDSCs-mediated T cell suppression.
Fig. 5: TNFSF15 regulates the differentiation of MDSC in vitro.
Fig. 6: TNFSF15 promotes MDSC differentiation through JAK1/STAT3 pathway.
Fig. 7: Schematic representation of TNFSF15-regulated MDSC differentiation.

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Acknowledgements

This study was supported in part by National Natural Science Foundation of China (82073064 and 81874167 to LYL; 82473963 to ZSZ), Haihe Laboratory of Cell Ecosystem Innovation Fund (22HHXBSS00020 to LYL), Ministry of Education 111 Project (B20016 to LYL), the Key Projects of Tianjin Science and Technology (24ZXZSSS00150 to ZSZ), and Key Laboratory of Immune Microenvironment and Disease (Ministry of Education) (116019-KJ01000601 to ZSZ).

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Authors and Affiliations

  1. State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, The Haihe Laboratory of Cell Ecosystem, Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, 300350, China

    Yi-pan Zhu, Jing Sun, Xin-yu Cao, Xin-yu Ding, Yu-ying Wang, Jing-ying Wang, Lu-yuan Li & Zhi-song Zhang

  2. School of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou, 310053, China

    Qiu-ju Han

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Contributions

YPZ performed most of the cellular, biochemical protein purification, and animal experiments. JS and XYD contributed to the cellular and animal experiments. YPZ and JS analyzed data; XYC, YYW, QJH, and JYW contributed to data analysis and chart analysis production. YPZ and JYW wrote the original manuscript. LYL and ZSZ initiated the project, led the project team, designed the experiment plans, analyzed the results.

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Correspondence to Jing-ying Wang, Lu-yuan Li or Zhi-song Zhang.

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Zhu, Yp., Sun, J., Cao, Xy. et al. TNFSF15 alleviates myeloid-derived suppressor cell-mediated cancer immunosuppression in mice. Acta Pharmacol Sin 47, 493–503 (2026). https://doi.org/10.1038/s41401-025-01663-y

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