Urolithin A Hijacks ERK1/2‐ULK1 Cascade to Improve CD8<sup>+</sup> T Cell Fitness for Antitumor Immunity
Shuaiya Ma, Qi Wu, Wenxian Wu, Ye Tian, Jie Zhang, Chaojia Chen, Xue Sheng, Fangcheng Zhao, Lu Ding, Taixia Wang, Laixi Zhao, Yuying Xie, Yongxiang Wang, Xuetian Yue, Zhuanchang Wu, Jian Wei, Kun Zhang, Xiaohong Liang, Lifen Gao, Hongyan Wang, Guihua Wang, Chunyang Li, Chunhong Ma
Abstract
Abstract According to the latest evidence, the microbial metabolite Urolithin A (UA), known for its role in promoting cellular health, modulates CD8 + T cell‐mediated antitumor activity. However, the direct target protein of UA and its underlying mechanism remains unclear. Here, this research identifies ERK1/2 as the specific target crucial for UA‐mediated CD8 + T cell activation. Even at low doses, UA markedly enhances the persistence and effector functions of primary CD8 + cytotoxic T lymphocytes (CTLs) and human chimeric antigen receptor (CAR) T cells both in vitro and in vivo. Mechanistically, UA interacts directly with ERK1/2 kinases, enhancing their activation and subsequently facilitating T cell activation by engaging ULK1. The UA‐ERK1/2‐ULK1 axis promotes autophagic flux in CD8 + CTLs, enhancing cellular metabolism and maintaining reactive oxygen species (ROS) levels, as evidenced by increased oxygen consumption and extracellular acidification rates. UA‐treated CD8 + CTLs also display elevated ATP levels and enhanced spare respiratory capacity. Overall, UA activates ERK1/2, inducing autophagy and metabolic adaptation, showcasing its potential in tumor immunotherapy and interventions for diseases involving ERKs.