Interleukin-33 alleviates the immunosuppressive tumor microenvironment and enhances anti–programmed death ligand-1 immunotherapy efficacy in hepatocellular carcinoma
Ensi Ma, Yange Gu, Weiqiao He, Yunshu Ma, Shengran Jiang, Quanbao Zhang, Xiaomu Hu, Jing Zhao, Zhengxin WangAbstract
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 (IL33) 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 IL33 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
Conclusion:
These findings indicate that IL-33 alleviates immunosuppression and enhances ICB efficacy, providing novel insights into its role in HCC immunotherapy.