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Peer-reviewedCC BY-NC-ND 4.0Chinese Medical Journal

Interleukin-33 alleviates the immunosuppressive tumor microenvironment and enhances anti-programmed death ligand-1 immunotherapy efficacy in hepatocellular carcinoma

  • Ensi Ma1
  • Yange Gu2
  • Weiqiao He3
  • Yunshu Ma4
  • Shengran Jiang1,2
  • Quanbao Zhang1,2
  • Xiaomu Hu5
  • Jing Zhao4,6
  • Zhengxin Wang1,2
6 affiliations
  1. 1Liver Transplantation Center, Department of General Surgery, Huashan Hospital, Fudan University, Shanghai 200040, China
  2. 2Institute of Organ Transplantation, Fudan University, Shanghai 200032, China
  3. 3Surgical Training Base, Huashan Hospital, Fudan University, Shanghai 200040, China
  4. 4Hepatobiliary Surgery Center, Department of General Surgery, Huashan Hospital, Fudan University, Shanghai 200040, China
  5. 5Department of Pathology, Huashan Hospital, Fudan University, Shanghai 200040, China
  6. 6Cancer Metastasis Institute, Fudan University, Shanghai 200032, China
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Abstract

Background:: Hepatocellular carcinoma (HCC) is one of the most lethal malignancies worldwide. The immunosuppressive tumor microenvironment (TME) and limited response to immune checkpoint blockade (ICB) therapy remain major obstacles to improving HCC prognosis. Interleukin-33 (IL-33) is a multifunctional cytokine that plays critical roles in cancer development; however, its function in HCC remains unclear.

Methods:: Cell proliferation was evaluated using colony formation and 5-ethynyl-2′-deoxyuridine (EdU) staining assays. Tumor-bearing models were established in both immunocompetent and immunodeficient mice. Multiplex immunofluorescence and flow cytometry were performed to assess TME characteristics. RNA sequencing and Western blot analyses were conducted to investigate the underlying mechanisms.

Results:: We found that IL-33 downregulation was significantly associated with shorter survival in patients with HCC. IL-33 treatment markedly inhibited tumor progression, whereas endogenous IL-33 blockade accelerated tumor growth in immunocompetent mice. However, IL-33 showed no significant effect on cell proliferation in vitro and failed to suppress tumor growth in immunodeficient mice lacking T cells. IL-33 administration notably reduced immunosuppressive tumor-associated macrophages and myeloid-derived suppressor cells, while substantially increasing CD8+ T cells, particularly functional interferon (IFN)-γ+CD8+ T cells, within the TME. Mechanistically, IL-33 activated the stimulator of interferon genes/interferon regulatory factor signaling axis, enhanced IFN-γ secretion, and inhibited Rictor and programmed death 1 expression in mouse tumors. Furthermore, HCC specimens with high IL-33 expression exhibited more tertiary lymphoid structures. In addition, combined IL-33 and anti-programmed death ligand-1 therapy synergistically reduced tumor burden and further enhanced antitumor immunity in vivo.

Conclusion:: These findings indicate that IL-33 alleviates immunosuppression and enhances ICB efficacy, providing novel insights into its role in HCC immunotherapy.

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Cite

BibTeXRIS
BibTeX
@article{ma2026interleukin33,
  title = {{Interleukin-33 alleviates the immunosuppressive tumor microenvironment and enhances anti-programmed death ligand-1 immunotherapy efficacy in hepatocellular carcinoma}},
  author = {Ensi Ma and Yange Gu and Weiqiao He and Yunshu Ma and Shengran Jiang and Quanbao Zhang and Xiaomu Hu and Jing Zhao and Zhengxin Wang},
  journal = {Chinese Medical Journal},
  year = {2026},
  month = sep,
  doi = {10.1097/cm9.0000000000004205},
  url = {https://doi.org/10.1097/cm9.0000000000004205},
  note = {CC BY-NC-ND 4.0},
}
RIS
TY  - JOUR
TI  - Interleukin-33 alleviates the immunosuppressive tumor microenvironment and enhances anti-programmed death ligand-1 immunotherapy efficacy in hepatocellular carcinoma
AU  - Ensi Ma
AU  - Yange Gu
AU  - Weiqiao He
AU  - Yunshu Ma
AU  - Shengran Jiang
AU  - Quanbao Zhang
AU  - Xiaomu Hu
AU  - Jing Zhao
AU  - Zhengxin Wang
PY  - 2026
DA  - 2026/09/22
JO  - Chinese Medical Journal
DO  - 10.1097/cm9.0000000000004205
UR  - https://doi.org/10.1097/cm9.0000000000004205
AB  - Background:: Hepatocellular carcinoma (HCC) is one of the most lethal malignancies worldwide. The immunosuppressive tumor microenvironment (TME) and limited response to immune checkpoint blockade (ICB) therapy remain major obstacles to improving HCC prognosis. Interleukin-33 (IL-33) is a multifunctional cytokine that plays critical roles in cancer development; however, its function in HCC remains unclear.  Methods:: Cell proliferation was evaluated using colony formation and 5-ethynyl-2′-deoxyuridine (EdU) staining assays. Tumor-bearing models were established in both immunocompetent and immunodeficient mice. Multiplex immunofluorescence and flow cytometry were performed to assess TME characteristics. RNA sequencing and Western blot analyses were conducted to investigate the underlying mechanisms.  Results:: We found that IL-33 downregulation was significantly associated with shorter survival in patients with HCC. IL-33 treatment markedly inhibited tumor progression, whereas endogenous IL-33 blockade accelerated tumor growth in immunocompetent mice. However, IL-33 showed no significant effect on cell proliferation in vitro and failed to suppress tumor growth in immunodeficient mice lacking T cells. IL-33 administration notably reduced immunosuppressive tumor-associated macrophages and myeloid-derived suppressor cells, while substantially increasing CD8+ T cells, particularly functional interferon (IFN)-γ+CD8+ T cells, within the TME. Mechanistically, IL-33 activated the stimulator of interferon genes/interferon regulatory factor signaling axis, enhanced IFN-γ secretion, and inhibited Rictor and programmed death 1 expression in mouse tumors. Furthermore, HCC specimens with high IL-33 expression exhibited more tertiary lymphoid structures. In addition, combined IL-33 and anti-programmed death ligand-1 therapy synergistically reduced tumor burden and further enhanced antitumor immunity in vivo.  Conclusion:: These findings indicate that IL-33 alleviates immunosuppression and enhances ICB efficacy, providing novel insights into its role in HCC immunotherapy.
SN  - 0366-6999
SN  - 2542-5641
ER  -