Leucine-derived isovaleric acid remodels the tumor microenvironment by degrading EIF3I.

Abstract

Metabolic reprogramming and immune evasion are hallmarks of cancer. Although leucine is well known for regulating protein synthesis, its role in immunometabolic interactions within the tumor microenvironment (TME) remains unclear. In this study, we found that leucine supplementation significantly inhibited tumor growth. Metabolomic analysis revealed that isovaleric acid (IVA) was the main differential metabolite produced during leucine degradation by the gut microbiota. Mechanistically, IVA directly binds to EIF3I at lysine 17 (K17), increasing its ubiquitination and promoting its proteasomal degradation. The degradation of EIF3I reduces the expression of SMAD3/p-SMAD3, thus suppressing the transcription of the chemokines CCL2 and CXCL12. The decreased expression of CCL2 and CXCL12 reduces the recruitment of myeloid-derived suppressor cell (MDSC) and restores the infiltration and cytotoxic activity of CD8+ T cells. Overall, our study reveals a novel immunometabolic axis linking isovaleric acid to tumor microenvironment remodeling and suggests that targeting EIF3I may represent a potential therapeutic strategy.