Amino acid metabolic reprogramming in clear cell renal cell carcinoma: Pathogenic mechanisms and therapeutic targeting.
- 2026-03
- Cancer letters 640
- Junzhe Xie
- Fangjing Ni
- Jialiang Shao
- Dongliang Zhang
- Tuanjie Guo
- Xiang Wang
- PubMed: 41494569
- DOI: 10.1016/j.canlet.2026.218244
Study Design
- Type
- Review
Kidney cancer is a major global health burden, with clear cell renal cell carcinoma (ccRCC) as the most common and aggressive subtype. Beyond the typical alterations of high glucose uptake and lipid accumulation, amino acid metabolism dysregulation in ccRCC is also gradually being uncovered. Pathways involving glutamine, cystine, serine, glycine, branched-chain amino acids, methionine, aspartate, arginine, proline and tryptophan are extensively rewired. These alterations enable cancer cells to sustain proliferation and biosynthesis, maintain redox balance, remodel the immune microenvironment, and develop resistance to therapy. At the same time, such reprogramming creates metabolic dependencies and vulnerabilities, including glutamine and cystine addiction as well as arginine auxotrophy. Dysregulation of key enzymes such as GLS1, ASS1 and IDO1 further highlights potential therapeutic targets. Exploiting these vulnerabilities through metabolic inhibitors or rational combinations with targeted and immunotherapy holds promise for overcoming resistance and improving outcomes in ccRCC.