PARK7 诱导的 ATAD3A 去乳酸化修饰损害线粒体适应性，从而促进肿瘤浸润 CD8(+) T 细胞的耗竭

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.