USP30 inhibition augments mitophagy to prevent T cell exhaustion

作者：Ruohan Zhang, Fengxia Gao, Jianying Li, Jiacheng Jin, Kangxuan Chen, Samhita Chaudhuri, Zhiwei Liao, Tong Xiao, Xu Yang, Haitao Wen, Kai He, Zihai Li, Gang Xin, Nuo Sun · 发表于：Science Advances · 年份：2025 · DOI：10.1126/sciadv.adv6902 · 被引用次数：13 · 研究领域：Autophagy in Disease and Therapy、Immune Cell Function and Interaction、Cytomegalovirus and herpesvirus research

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.