epacadostat (INCB024360)

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.

P2, N=33, Not yet recruiting, Changhai Hospital

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

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.

CAFs suppressed T-cell proliferation and induced PD-1 expression in CD4+ and CD8+ T cells, effects reversed by epacadostat. IDO1 inhibition enhanced T-cell proliferation via AKT signaling, restored T-cell cytotoxicity, and increased ovarian cancer cell apoptosis. These findings suggest that targeting IDO1 may help counteract CAF-mediated immunosuppression and enhance antitumor immunity in HGSOC.

Among these, medications like Indoximod, Epacadostat, and Navoximod have shown promise in influencing the immune system and slowing tumor progression, while dual inhibitors like HTI-1090 try to address broader metabolic connections. The use of IDO/TDO inhibitors with conventional anticancer medications demonstrates their potential to reshape cancer treatment paradigms, contingent on further research to optimize efficacy and safety. Clinical Trial Registration: https://clinicaltrials.gov/study/NCT03844438.