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PARK7-induced delactylation of ATAD3A impairs mitochondrial fitness to promote exhaustion of tumor-infiltrating CD8+ T cells

Cellular & Molecular Immunology (2026) Cite this article

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Abstract

Mitochondrial dysfunction is a critical factor driving the exhaustion of tumor-infiltrating CD8+ T cells and impeding the efficacy of tumor immunotherapy. However, the key regulatory proteins and molecular mechanisms governing mitochondrial function in CD8+ T cells remain enigmatic. Here, we report that PARK7 is significantly enriched in the mitochondria of tumor-infiltrating CD8+ T cells. T-cell-specific PARK7 deficiency enhanced mitochondrial function in CD8+ T cells, alleviated T-cell exhaustion, and suppressed tumor growth. Mechanistically, we found that PARK7 directly interacted with the mitochondrial membrane protein ATAD3A and downregulated its lactylation level, thereby suppressing the expression of mitochondrial-related genes and ultimately promoting CD8+ T-cell exhaustion. Overall, our study not only identifies the critical role of PARK7 in regulating mitochondrial function in CD8+ T cells but also elucidates the molecular mechanism through which the PARK7-ATAD3A axis modulates mitochondrial gene expression, providing a potential therapeutic strategy for targeting PARK7 in tumor immunotherapy.

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Data availability

Raw data files from the scRNA-seq experiments were submitted to the Genome Sequence Archive (GSA) website (https://ngdc.cncb.ac.cn/gsub/), which is affiliated with the National Genomics Data Center (https://ngdc.cncb.ac.cn/), under accession number (sub CRA032203). The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Acknowledgements

This study was funded by the National Natural Science Foundation of China (NSFC) (82503149, 82271807, and 82471810), the Key Science and Technology Project of Hubei Provincial Health Commission (WJ2025Z020), the Nonprofit Central Research Institute Fund of China (2023-PT320-07), the Key R&D Program of the Department of Science and Technology of Hubei Province, China (2023BCB013), and the Hubei Provincial Natural Science Foundation (No. 2025AFD793).

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  1. These authors contributed equally: Jing Liu, Mengjun Xu, Yi Zhou.

Authors and Affiliations

  1. Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology; Key Laboratory of Organ Transplantation, Ministry of Education; NHC Key Laboratory of Organ Transplantation; Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences; Organ Transplantation Clinical Medical Research Center of Hubei Province, Wuhan, China

    Jing Liu, Mengjun Xu, Yi Zhou, Jiahao Li, Xi Zhou, Zhibo Ma, Qingwen Li, Yuhang Wang, Sichuan Yi, Naonao Yuan, Zhishui Chen & Peixiang Lan

  2. Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

    Hua Xiong

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Contributions

Peixiang Lan and Hua Xiong conceived and designed the study. Jing Liu, Mengjun Xu and Yi Zhou performed most of the experiments and data acquisition. Jiahao Li, Xi Zhou, Zhibo Ma, Qingwen Li, Yuhang Wang, Sichuan Yi and Naonao Yuan assisted with the experiments and data acquisition. Zhishui Chen and Xi Zhou contributed to the design of the experimental methods and participated in data collection. Mengjun Xu and Jiahao Li were involved in data collection. Peixiang Lan and Jing Liu wrote the manuscript. Peixiang Lan, Hua Xiong and Jing Liu provided funding for this project.

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Correspondence to Hua Xiong or Peixiang Lan.

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Liu, J., Xu, M., Zhou, Y. et al. PARK7-induced delactylation of ATAD3A impairs mitochondrial fitness to promote exhaustion of tumor-infiltrating CD8+ T cells. Cell Mol Immunol (2026). https://doi.org/10.1038/s41423-026-01425-8

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