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<p>Mitochondrial dysfunction is a critical factor driving the exhaustion of tumor-infiltrating CD8<sup>+</sup> T cells and impeding the efficacy of tumor immunotherapy. However, the key regulatory proteins and molecular mechanisms governing mitochondrial function in CD8<sup>+</sup> T cells remain enigmatic. Here, we report that PARK7 is significantly enriched in the mitochondria of tumor-infiltrating CD8<sup>+</sup> T cells. T-cell-specific PARK7 deficiency enhanced mitochondrial function in CD8<sup>+</sup> 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<sup>+</sup> T-cell exhaustion. Overall, our study not only identifies the critical role of PARK7 in regulating mitochondrial function in CD8<sup>+</sup> 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.</p>

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

  • 期刊论文

  • 发表日期：

    2026年5月20日

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

摘要

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.