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Translational Therapeutics

Oxaliplatin induces pyroptosis in hepatoma cells and enhances antitumor immunity against hepatocellular carcinoma

British Journal of Cancer volume 132, pages 371–383 (2025)Cite this article

Subjects

Abstract

Background

Pyroptosis is closely associated with chemotherapeutic drugs and immune response. Here, we investigated whether oxaliplatin, a key drug in FOLFOX-hepatic artery infusion chemotherapy (FOLFOX-HAIC), induces pyroptosis in hepatoma cells and enhances antitumor immunity after tumor cell death.

Methods

Hepatoma cells were treated with oxaliplatin. Pyroptosis and immunoreactivity were evaluated in vitro and in vivo.

Results

Oxaliplatin activated caspase-3-mediated gasdermin E (GSDME) cleavage and induced pyroptosis in Hep G2 and SK-Hep-1 cells in vitro. Liver cancer cells with high levels of GSDME expression are prone to pyroptosis. Bioinformatic analysis revealed that pyrolysis-related genes are closely related to immunity. In vivo experiments revealed that oxaliplatin exhibited superior antitumor efficacy in mice with normal immune function and more pronounced inhibitory effect on hepatocellular carcinoma with high GSDME levels. Higher levels of cytokines and greater CD8+ T cell infiltration were observed in tumor tissues with better efficacy. Furthermore, an in vitro coculture assay confirmed that oxaliplatin-induced pyroptosis in Hep G2 cells overexpressing GSDME and activated the p38/MAPK signaling pathway to improve the cytotoxicity of CD8+ T cells. Analysis of clinical samples of HCC suggested that the efficacy of FOLFOX-HAIC in patients with high GSDME expression was better than that in patients with low GSDME expression.

Conclusions

Oxaliplatin induced pyroptosis in hepatoma cells by activating caspase-3-mediated cleavage of GSDME, which enhanced the cytotoxicity of CD8+ T cells by regulating the p38/MAPK signaling pathway. These results suggest that GSDME level may be used as a marker to predict the efficacy of FOLFOX-HAIC.

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Fig. 1: Oxaliplatin inhibits cell viability and induces pyroptosis in hepatoma cells.
Fig. 2: Oxaliplatin induces pyroptosis in hepatoma cells through caspase-3 cleavage of GSDME.
Fig. 3: GSDME overexpression promotes oxaliplatin-induced pyroptosis.
Fig. 4: GSDME-mediated pyroptosis enhances antitumor immune response.
Fig. 5: GSDME-mediated pyroptosis enhances CD8+ T cell killing capability via activation of the p38/MAPK pathway.
Fig. 6: Levels of GSDME predict the efficacy of FOLFOX-HAIC in HCC patients.
Fig. 7: Schematic illustration of the proposed mechanism.

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Data availability

All data associated with this study are present within the main text or the Supplementary Materials.

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Acknowledgements

We are grateful to all patients and healthy participants for their involvement. We would like to thank Figdraw (www.figdraw.com).

Funding

This study was supported by the National Natural Science Foundation of China (No. 82303156, No. 82172579); Science and Technology Planning Project of Guangzhou (No. 2023A04J1777, No. 2023A04J1781); Clinical Trials Project (5010 Project) of Sun Yat-sen University (No. 5010-2017009, No. 5010-2023001).

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Author notes

  1. These authors contributed equally: Min Deng, Rongce Zhao, Hao Zou, Renguo Guan

Authors and Affiliations

  1. Department of Liver Surgery, Sun Yat-sen University Cancer Center, Guangzhou, China

    Min Deng, Rongce Zhao, Hao Zou, Jiongliang Wang, Benyi He, Shaohua Li, Wei Wei & Rongping Guo

  2. State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China

    Min Deng, Rongce Zhao, Hao Zou, Jiongliang Wang, Benyi He, Jing Zhou, Shaohua Li, Wei Wei & Rongping Guo

  3. Department of General Surgery, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China

    Min Deng

  4. Department of General Surgery, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China

    Renguo Guan

  5. School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, Hong Kong, China

    Carol Lee

  6. Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou, China

    Jing Zhou

  7. Department of General Surgery, Department of Transplantation, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China

    Hao Cai

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Contributions

M. Deng, R. Zhao, and R. Guo were involved in the study conceptualization; M. Deng, R. Zhao, H. Zou, J. Wang, C. Lee, H. Cai and R. Guo contributed in the investigation and methodology; M. Deng, H. Zou, J. Wang, R. Guan, B. He, and J. Zhou performed the experiments; M. Deng, H. Zou, and H. Cai contributed in data curation and software analysis; M. Deng, R. Zhao, S. Li, W. Wei, H. Cai, and R. Guo contributed in formal analysis; M. Deng, R. Guan, and B. He collected the clinical samples; W. Wei and R. Guo provided supervision. H. Cai, W. Wei and R. Guo contributed in funding acquisition; M. Deng, H. Zou, R. Zhao, R. Guan, H. Cai, and R. Guo prepared the manuscript; All authors were involved in the critical review and editing of the manuscript.

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Correspondence to Hao Cai or Rongping Guo.

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Informed consent was obtained from all patients included in this study. The research was carried out according to the World Medical Association Declaration of Helsinki and approved by the Institutional Ethical Review Board of the SYSUCC (B202031801). The animal procedures were approved by the Institutional Animal Care and Use Committee of Sun Yat-sen University Cancer Center (L102042022020D).

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Deng, M., Zhao, R., Zou, H. et al. Oxaliplatin induces pyroptosis in hepatoma cells and enhances antitumor immunity against hepatocellular carcinoma. Br J Cancer 132, 371–383 (2025). https://doi.org/10.1038/s41416-024-02908-z

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