USP30 inhibition augments mitophagy to prevent T cell exhaustion.

Abstract The quality control of mitochondria through mitophagy is crucial for maintaining effective anti-tumor CD8 T cell responses. However, this process is compromised during T cell exhaustion. The specific mechanisms regulating mitophagy remain unclear, hindering efforts to target it for reversing T cell dysfunction. To tackle this challenge, we employed a mitophagy-reporter mouse model and revealed impaired mitophagy activity in exhausted CD8 T cells exhibiting mitochondrial dysfunction. Through a bioinformatic and experimental approach, we identified that USP30, a mitochondrial deubiquitinase inhibiting mitophagy, is upregulated in exhausted CD8 T cells with the decline of mitophagy. Genetic deletion or pharmacological inhibition of USP30 can significantly enhance mitophagy in exhausted CD8 T cells and restore their mitochondrial fitness and effector function, ultimately reinvigorating anti-tumor CD8 T cell responses and enhancing immunity against tumors. Furthermore, our observations indicated that the stimulation of the T-cell receptor amplifies the transcription of USP30 in exhausted CD8 T cells, highlighting its pivotal role in regulating mitophagy. Overall, our findings shed light on the vital role of USP30-regulated mitophagy in controlling mitochondrial quality during T cell exhaustion while also providing valuable insights into developing targeted therapies to restore mitophagy, thereby improving the immune response against tumors.