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Urolithin A Hijacks ERK1/2‐ULK1 Cascade to Improve CD8+ T Cell Fitness for Antitumor Immunity
- Source :
- Advanced Science, Vol 11, Iss 18, Pp n/a-n/a (2024)
- Publication Year :
- 2024
- Publisher :
- Wiley, 2024.
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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.
- Subjects :
- autophagy
CAR T cells
CD8+ cytotoxic T cells
ERK1/2
Urolithin A (UA)
Science
Subjects
Details
- Language :
- English
- ISSN :
- 21983844
- Volume :
- 11
- Issue :
- 18
- Database :
- Directory of Open Access Journals
- Journal :
- Advanced Science
- Publication Type :
- Academic Journal
- Accession number :
- edsdoj.657c653a712841f89996f5fb75da0840
- Document Type :
- article
- Full Text :
- https://doi.org/10.1002/advs.202310065