Hepatocellular carcinoma (HCC) is a highly lethal cancer with increasing incidence rates worldwide. The recommended treatments for advanced‑stage HCC are sorafenib and regorafenib; however, developing resistance to these medications significantly limits their effectiveness, and the underlying mechanisms are poorly understood. The present study demonstrated that interleukin‑33 (IL‑33) promotes sorafenib resistance via immune regulation. In vitro, western blotting and reverse transcription‑quantitative PCR showed that both sorafenib and regorafenib treatments led to an increase in the upregulation and secretion of IL‑33 through a positive feedback loop involving the IL‑33/transmembrane suppression of tumorigenicity 2 (ST2L) pathway. Senescence‑associated β‑galactosidase staining and western blotting revealed that sorafenib and regorafenib treatments induce cell senescence in HCC cells. Flow cytometric analysis indicated that he secreted IL‑33 enhanced programmed cell death ligand 1 (PD‑L1) expression in HCC cells by activating NF‑κB pathways in response to the treatments. In vivo, a HCC‑bearing subcutaneous mouse model revealed that blocking the IL‑33 signaling pathway with anti‑IL‑33 or anti‑ST2L neutralizing antibodies, combined with sorafenib, significantly reduced tumor size, growth rate, and weight. Additionally, there was a notable decrease in tumor PD‑L1 expression and an increase in intra‑tumor CD8⁺ T cells infiltration. Importantly, the enhanced therapeutic efficacy of the anti‑IL‑33 treatment in sorafenib‑treated HCC‑bearing mice was lost in immunocompromised mice. This indicates that the anti‑IL‑33 neutralizing antibody enhances the antitumor activity of sorafenib by modulating the immune response rather than directly affecting HCC cell proliferation. The findings of the present study suggested that IL‑33 plays a role in decreasing the therapeutic effectiveness of sorafenib and regorafenib in HCC cells. The present study highlights the potential of targeting the IL‑33/ST2L axis in combination with targeted therapies as a novel strategy to improve the limited efficacy of sorafenib and regorafenib.

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