Decoding IL4I1: The Core role of metabolism-driven immune regulation and new perspectives on disease targeting

Interleukin-4-induced protein 1 (IL4I1) is a secreted L-amino acid oxidase primarily produced by antigen-presenting cells and aberrantly expressed in tumors and tumor-associated immune cells. It catalyzes the oxidative deamination of aromatic amino acids (L-phenylalanine, tryptophan, and tyrosine), generating hydrogen peroxide, ammonia, keto acids, and immunomodulatory indole derivatives such as indole-3-pyruvate, which activate the aryl hydrocarbon receptor (AHR). Through its enzymatic activity and metabolites, IL4I1 suppresses T-cell proliferation and effector functions, promotes regulatory T cell (Treg) differentiation, and negatively regulates B-cell (BCR) and T-cell receptor (TCR) signaling. These mechanisms facilitate tumor immune escape, promoting cancer progression, metastasis, and resistance to immunotherapy. Beyond oncology, IL4I1 is implicated in autoimmune, infectious, and inflammatory diseases, underscoring its role as a critical metabolic immune checkpoint. Consequently, IL4I1 emerges as a significant prognostic biomarker and a promising therapeutic target, driving ongoing development of targeted inhibitors. This review comprehensively synthesizes the structural, functional, and clinical landscape of IL4I1, highlighting its therapeutic potential.