Targeting GSDME-mediated macrophage polarization for enhanced antitumor immunity in hepatocellular carcinoma | Cellular & Molecular Immunology

Nov 04, 2024

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Despite the notable efficacy of anti-PD1 therapy in the management of hepatocellular carcinoma (HCC) patients, resistance in most individuals necessitates additional investigation. For this study, we collected tumor tissues from nine HCC patients receiving anti-PD1 monotherapy and conducted RNA sequencing. These findings revealed significant upregulation of GSDME, which is predominantly expressed by tumor-associated macrophages (TAMs), in anti-PD1-resistant patients. Furthermore, patients with elevated levels of GSDME+ macrophages in HCC tissues presented a poorer prognosis. The analysis of single-cell sequencing data and flow cytometry revealed that the suppression of GSDME expression in nontumor cells resulted in a decrease in the proportion of M2-like macrophages within the tumor microenvironment (TIME) of HCC while concurrently augmenting the cytotoxicity of CD8 + T cells. The non-N-terminal fragment of GSDME within macrophages combines with PDPK1, thereby activating the PI3K-AKT pathway and facilitating M2-like polarization. The small-molecule Eliprodil inhibited the increase in PDPK1 phosphorylation mediated by GSDME site 1. The combination of Eliprodil and anti-PD1 was effective in the treatment of both spontaneous HCC in c-Myc + /+;Alb-Cre + /+ mice and in a hydrodynamic tail vein injection model, which provides a promising strategy for novel combined immunotherapy.

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The necessary data for assessing the conclusions are provided within the paper or supplementary information. Data pertaining to public databases can be obtained by referring to the specified address. Additional data supporting the findings of this study may be appropriately requested from the corresponding authors.

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This study was supported by the National Natural Science Foundation of China (No. 82372946, No. 82072670, and No. 81871916), the Leading Project of the Science and Technology Committee of Shanghai Municipality (No. 21Y21900100), and the Project of Shanghai Municipal Health Commission (No. 202140269). We express our gratitude for the drawing model library made available by the Figdraw platform and for the complimentary provision of mouse illustrations by the Nanfang Model Organisms Center (Shanghai).

These authors contributed equally: Shiping Chen, Peiling Zhang, Guiqi Zhu, Biao Wang.

Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, China; Key Laboratory of Carcinogenesis and Cancer Invasion, Fudan University, Ministry of Education, Shanghai, 200032, China

Shiping Chen, Peiling Zhang, Jialiang Cai, Lina Song, Jinglei Wan & Zhi Dai

State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, 200032, China

Shiping Chen, Peiling Zhang, Jialiang Cai, Lina Song, Jinglei Wan & Zhi Dai

Department of Liver Surgery and Transplantation, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Shanghai, China

Guiqi Zhu, Jian Zhou & Jia Fan

Research Unit of Liver Cancer Recurrence and Metastasis, Chinese Academy of Medical Sciences, Beijing, China

Guiqi Zhu, Jian Zhou & Jia Fan

Department of Radiation Oncology, Zhongshan Hospital, Fudan University, Shanghai, China

Biao Wang & Yi Yang

Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032, China

Junxian Du & Yufan Cai

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In this study, Jia Fan, Jian Zhou, and Zhi Dai were responsible for the study design, supervision, and manuscript review. Peiling Zhang and Guiqi Zhu contributed to the experimental design, provision of reagents, and study coordination. Shiping Chen primarily conducted the molecular biology and in vitro functional analysis experiments, whereas Biao Wang and Jialiang Cai were primarily involved in the animal experiments. Lina Song, Jinglei Wan, and Yi Yang analyzed the bioinformatics data and assisted in generating graphics and typesetting. Junxian Du and Yufan Cai participated in a portion of the experimental research.

Correspondence to Zhi Dai.

The authors declare no competing interests.

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Chen, S., Zhang, P., Zhu, G. et al. Targeting GSDME-mediated macrophage polarization for enhanced antitumor immunity in hepatocellular carcinoma. Cell Mol Immunol (2024). https://doi.org/10.1038/s41423-024-01231-0

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Received: 18 April 2024

Revised: 23 September 2024

Accepted: 13 October 2024

Published: 04 November 2024

DOI: https://doi.org/10.1038/s41423-024-01231-0

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