IDO family: the metabolic crossroads connecting immunity, nerves and tumors.

[BACKGROUND] Tryptophan metabolism is essential for immune homeostasis, neurological function regulation, and tumor microenvironment modulation. The indoleamine 2,3-dioxygenase (IDO) family, including IDO1, IDO2, and tryptophan 2,3-dioxygenase (TDO2), serves as the rate-limiting enzymes in the kynurenine pathway of tryptophan catabolism. These enzymes act as a critical molecular hub linking immune metabolism, neural regulation, and tumorigenesis, and their aberrant activity is closely associated with the pathogenesis of various diseases such as tumors, autoimmune disorders, infectious diseases, and neurological conditions. Although IDO family inhibitors have shown potential in cancer immunotherapy, clinical trial results remain controversial, highlighting the complexity of their mechanisms and the need for systematic summarization of relevant research progress.

[MAIN BODY] This review first elaborates on the structural characteristics, tissue distribution, catalytic efficiency, and core biological functions of IDO1, IDO2, and TDO2, emphasizing their distinct and complementary roles in tryptophan metabolism and immune regulation. It then systematically summarizes the regulatory mechanisms of the IDO family at transcriptional, translational, and post-translational levels. Subsequently, the review details the roles of each family member in different disease contexts: IDO1 predominantly mediates local immunosuppression and tumor immune escape; IDO2 drives B cell-related inflammation and autoimmune responses; TDO2 maintains systemic tryptophan homeostasis and links neurometabolism to immunity. Additionally, the article comprehensively discusses current therapeutic strategies targeting the IDO family, including small-molecule inhibitors (single-target, dual-target, and multi-target), peptide vaccines, and nano-delivery systems, while analyzing the challenges faced in clinical translation, such as pathway compensation, insufficient patient stratification, and off-target effects.

[CONCLUSIONS] The IDO family plays a multifaceted and context-dependent role in various diseases through the kynurenine pathway, making it a promising target for diagnostic biomarkers and therapeutic intervention. Future research should focus on optimizing multi-target inhibitors, developing innovative delivery systems, establishing biomarker-guided precision medicine strategies, and exploring non-enzymatic functions and downstream signaling networks of the IDO family. These efforts will help overcome the limitations of current therapies and provide new treatment paradigms for refractory diseases related to immune metabolic disorders.