| First Author | Zhang R | Year | 2025 |
| Journal | Sci Adv | Volume | 11 |
| Issue | 33 | Pages | eadv6902 |
| PubMed ID | 40815646 | Mgi Jnum | J:373358 |
| Mgi Id | MGI:8239181 | Doi | 10.1126/sciadv.adv6902 |
| Citation | Zhang R, et al. (2025) USP30 inhibition augments mitophagy to prevent T cell exhaustion. Sci Adv 11(33):eadv6902 |
| abstractText | The exhaustion of tumor-infiltrating CD8(+) T cells poses a substantial challenge in cancer immunotherapy, with mitochondrial health essential for sustaining T cell functionality. Mitophagy, a critical process for mitochondrial quality control, is severely impaired in exhausted CD8(+) T cells, yet the underlying mechanisms remain unclear. We identified ubiquitin-specific protease 30 (USP30), a mitochondrial deubiquitinase that inhibits mitophagy, as a key factor up-regulated in exhausted CD8(+) T cells. Notably, prolonged antigen stimulation triggers the T cell receptor and nuclear factor of activated T cell 1 signaling, which drives the transcriptional up-regulation of USP30. Excitingly, our interventions targeting USP30 through genetic deletion or pharmacological inhibition effectively restored mitophagy, improved mitochondrial fitness, and rejuvenated CD8(+) T cell effector functions. These interventions reinvigorated antitumor responses and markedly suppressed tumor growth. Our findings establish USP30 as a critical regulator of mitophagy and a promising therapeutic target for reversing T cell exhaustion and enhancing the efficacy of cancer immunotherapy. |
