USP30 inhibition augments mitophagy to prevent T cell exhaustion
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
Abstract
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.