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...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.

Kyn pathway enzyme expression varies with disease progression and may indicate immune activity by influencing tumor microenvironment catabolites. BC cell sensitivity to immune stimuli differs, potentially shaping distinct immune escape mechanisms.

P2, N=30, Active, not recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: Jan 2026 --> Jan 2027

P1/2, N=50, Terminated, Incyte Corporation | N=136 --> 50

Notably, the dual inhibition of IDO1 and PARP1/2 specifically reduced the expression of HR core genes and proteins, such as BRCA1 and RAD51, which may contribute to impaired DNA-damage repair and increased sensitivity to Olaparib. In summary, targeting both IDO1 and PARP1/2 represents a promising combination therapy for BRCA-proficient TNBC.

P3, N=855, Active, not recruiting, Bristol-Myers Squibb | Trial primary completion date: Nov 2025 --> Feb 2026

P2, N=10, Not yet recruiting, Tianjin Third Central Hospital; Tianjin Third Central Hospital

P2, N=9, Not yet recruiting, University Hospital, Basel, Switzerland

P3, N=89, Completed, Incyte Corporation | Active, not recruiting --> Completed

P2, N=51, Completed, Washington University School of Medicine | Active, not recruiting --> Completed | Trial completion date: Apr 2026 --> Oct 2025

By studying the turnover of IDO1 protein in human tumor cells exposed to various IDO1 catalytic inhibitors, such as epacadostat, linrodostat, and navoximod, we show here that these molecules stabilize a non-enzymatic protein conformation of IDO1, independently of their mechanism of inhibition. In the thyroid carcinoma cell line FTC-133, the stabilized and non-enzymatic IDO1 protein promotes the proliferation and migration of the tumor, resulting in an adverse pro-tumorigenic effect. These results uncover an unexpected adverse effect of IDO1 inhibitors in the tumor microenvironment that overcomes the enzymatic inhibition of IDO1, and suggest protein degradation, rather than enzymatic inhibition, as a more effective approach to target IDO1 in the tumor microenvironment.

These findings suggest a potential inhibitory mechanism for PF-06840003 and offer valuable structural insights for the rational design of potent IDO1 inhibitors. It should be noted that the inhibitory activity of the designed lead compounds is based solely on computational predictions; experimental validation through in vitro and in vivo studies is still required to confirm their actual inhibitory effects and pharmacokinetic properties.