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

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.