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Targeting TFAM downregulation mediated mtDNA-NLRP3 pathway suppresses TAM infiltration and HCC progression

Oncogene (2025)Cite this article

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Abstract

The infiltration of TAMs mediates an immunosuppressive tumor microenvironment, which plays a crucial role in the malignant progression of HCC. TFAM is a key molecule that regulates mtDNA replication and transcription, and its expression frequently downregulated in various tumors, including HCC. Our previous study indicated that the downregulation of TFAM triggers mtDNA stress, thereby inducing autophagy and promoting ESCC survival through the STING pathway. However, it remains unclear whether cytosolic mtDNA stress, mediated by TFAM downregulation, is implicated in microenvironment regulation, particularly in the infiltration of TAMs in HCC. In this study, we found that TFAM expression was significantly decreased and correlated with CD163 expression in HCC tissues. The downregulated expression of TFAM in HCC cells contributed to TAM infiltration. Mechanistically, the downregulation of TFAM induced cytosolic mtDNA stress, which activated the NLRP3 inflammasome and promoted the expression of IL-18 and IL-1β in HCC cells, thereby inducing macrophage recruitment and M2 polarization. Depleting cytosolic mtDNA using DNase I or blocking NLRP3 inflammasome activation with an NLRP3 antagonist in HCC cells with TFAM downregulation significantly suppresses the infiltration of M2-TAMs. Moreover, blocking the mtDNA-NLRP3 pathway significantly inhibited TAM infiltration and orthotopic mouse HCC model progression. Taken together, our results reveal a novel mechanism by which cytosolic mtDNA stress mediates TAM infiltration in HCC.

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Fig. 1: Downregulation of TFAM is associated with poor prognosis and macrophage infiltration in HCC.
Fig. 2: Downregulated TFAM significantly contributes to the recruitment and polarization of macrophages.
Fig. 3: Downregulated TFAM crucially promotes mtDNA stress in HCC cells.
Fig. 4: Blocking mtDNA stress in HCC cells inhibits TAMs recruitment and polarization.
Fig. 5: Downregulated TFAM mediates NLRP3 inflammasome activation to promote macrophage infiltration.
Fig. 6: Blocking mtDNA stress inhibits NLRP3 inflammasome activation in HCC cells.
Fig. 7: Targeted blockade of the mtDNA-NLRP3 pathway inhibits TAM infiltration and HCC progression.
Fig. 8: Schematic depicting of this article.

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Data availability

The data that support the findings of this study are available on request from the corresponding author Dengke Bao ([email protected]).

Code availability

The data that support the findings of this study are available on request from the corresponding author Dengke Bao ([email protected]).

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (grant number 82373070 and 82002511). The Youth Promotion Project of Zhongzhou Laboratory for Integrative Biology (grant number 2024TS0101 and 2024TS0106). Postdoctoral Fellowship Program of CPSF (grant number GZC20230692), Excellent Youth Fund Project of Henan Natural Science Foundation (grant number 232300421043), Scientific and Technological Project of Henan Province in China (grant number SBGJ202302086 and 242102311046) and young backbone teachers of colleges and universities in Henan province (grant number 2021GGJS027), and Program for Central Plains Youth Top Talent for DKB, and Henan Postdoctoral Scientific Research Program (HN2025014).

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Author notes

  1. These authors contributed equally: Jing Zhao, Mengmeng Cui, Xiaojuan Yao.

Authors and Affiliations

  1. Laboratory of Cancer Biomarkers and Liquid Biopsy, School of Pharmacy, Henan University, Kaifeng, 475000, Henan, China

    Jing Zhao, Mengmeng Cui, Xiaojuan Yao, Zhixiong Jiang, Lixia Qi, Jiaxing Chen, Chunhui Fan, Hongliang Liu, Qi Yang & Dengke Bao

  2. The Zhongzhou Laboratory for Integrative Biology, Henan University, Zhengzhou, Henan, 450000, China

    Jing Zhao & Dengke Bao

  3. Henan Engineering Research Center for Molecular Diagnosis and Therapy of Esophageal Cancer, Nanyang central Hospital, Henan University, Nanyang, Henan, 473000, China

    Jing Zhao, Lixin Wan & Dengke Bao

  4. State key Laboratory of Antiviral Drugs, School of Pharmacy, Henan University, Kaifeng, Henan, 475000, China

    Mengmeng Cui, Xiaojuan Yao, Zhixiong Jiang, Lixia Qi, Jiaxing Chen, Chunhui Fan, Hongliang Liu & Dengke Bao

  5. First Affiliated Hospital of Henan University, Kaifeng, Henan, 475000, China

    Shuwen Bai, Qi Yang & Dengke Bao

  6. Huaihe Hospital of Henan University, Kaifeng, Henan, 475000, China

    Chengying Zhou & Rui Wei

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Contributions

DKB and JZ performed the experiments and data analysis. JZ and XJY wrote this article. This article was revised by LXW, QY. HLL and MMC conceived and designed the study. ZXJ, LXQ, JXC., CHF, SWB, CYZ and RW helped with the data analysis. All authors read and approved the manuscript.

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Correspondence to Qi Yang, Lixin Wan or Dengke Bao.

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Zhao, J., Cui, M., Yao, X. et al. Targeting TFAM downregulation mediated mtDNA-NLRP3 pathway suppresses TAM infiltration and HCC progression. Oncogene (2025). https://doi.org/10.1038/s41388-025-03467-0

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