Current applications and development of dual-target inhibitors of Ido1/TDO: From tumor immunology to neuropsychiatric disorders.

Indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase (TDO) are rate-limiting enzymes of the kynurenine pathway and are closely associated with tumor immune evasion and neuropsychiatric disorders. The failure of single-target IDO1 inhibition, exemplified by the phase III setback of epacadostat, has highlighted the limitations imposed by compensatory TDO activity and the heterogeneity of the tumor microenvironment. This review focuses on three generations of IDO1 inhibitors, selective TDO inhibitors, and emerging dual-target strategies, and provides a comprehensive overview of IDO1/TDO dual-target inhibitors. We summarize the research progress of β-carboline, indazole, indole, isoquinoline/alkaloid-derived, and other natural product-related scaffolds, with particular emphasis on their structure-activity relationships, binding modes, translational pharmacology, and preclinical efficacy in tumor and central nervous system models. Clinical-stage candidates have further demonstrated the translational potential of simultaneous IDO1/TDO blockade. Overall, this review offers new insights and strategic perspectives for therapeutic paradigms spanning cancer immunotherapy and neuropsychiatric intervention through modulation of the integrated immunity-metabolism-neurology axis.