TDO2 (Tryptophan 2,3-Dioxygenase)

These niches shape local TRP availability, metabolite gradients, downstream metabolic signaling, and immune responses in ways that cannot be captured by bulk or single-cell approaches alone. This review synthesizes emerging insights into the diverse and spatially defined functions of TRP metabolism in cancer and discusses how integrating spatial omics may guide next-generation therapeutic strategies beyond IDO1 inhibition.

Finally, we discuss therapeutic directions spanning AQP4 modulation, isoform balance, and BBB-bypassing delivery strategies. Overall, AQP4 emerges as a mechanistic hub connecting BBB instability, glymphatic impairment, edema, immune evasion, and invasion in GBM.

Tryptophan-kynurenine enzymes shape the immune landscape of EC in a subtype-specific manner. High IDO1 was linked to favourable outcomes in p53mut and NSMP cases, whereas TDO2 predicted poor prognosis. The CD163:CD8 ratio emerged as an independent marker of poor survival. These findings support therapeutic strategies combining dual IDO1/TDO2 inhibition or targeting the IL4I1- aryl hydrocarbon receptor (AhR) axis to enhance immunotherapy efficacy in EC.

Quercetin, paclitaxel, and cisplatin exert anti-proliferative and anti-migratory effects on GC cells, potentially associated with the suppression of IDO1-mediated tryptophan metabolism.

Furthermore, at a concentration of 5 μM, the compounds significantly suppressed the lipopolysaccharide-induced proinflammatory cytokines production in macrophages. These findings identify a novel chemical scaffold with dual inhibitory activity against IDO1/TDO and anti-inflammatory effects, suggesting potential for therapeutic application in cancer and inflammatory diseases.

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.

Moreover, despite the propensity of the imidazole motif to inhibit cytochrome P450 enzymes (CYP), we were able to discover potent IDO1 inhibitors devoid of CYP inhibition. Imidazo[1,5-a]pyrazine (R)-100 has an overall suitable profile, which warrants further investigation.

This synthesis pinpoints microglial and endothelial KYN hotspots, quantifies sex-specific chronotherapeutic windows, and identifies engineered Bifidobacterium consortia and dual inhibitors as synergistic nodes capable of reducing immunosuppressive KYN while preserving neuroprotective kynurenic acid. Here, we highlight a framework that couples lifestyle levers, bio-engineered microbes, and adaptive pharmaco-regimens into closed-loop "smart protocols." By charting these intersections, this study offers a roadmap for biomarker-guided, multidisciplinary interventions that could recalibrate KYN metabolic activity across cancer, mood, neurodegeneration, and metabolic disorders, appealing to clinicians, bioengineers, and systems biologists alike.

Our findings provide novel insights into the EOC metabolic and protein landscape. We developed and validated a plasma classifier demonstrating high sensitivity and specificity, which effectively distinguishes EOC patients from non-OC individuals. This classifier could enhance preoperative diagnostic accuracy and aid in differential diagnosis.

IDO1 mediates the malignant biological behavior of cervical cancer cells through the tryptophan-kynurenine pathway, suggesting its potential as a therapeutic target in cervical malignancies.

Drug sensitivity analysis revealed that BTN3A1, SIRPA, and TDO2 were correlated with the efficacy of several antineoplastic agents, including hydroxyurea and docetaxel. Validation in our clinical cohort highlighted the significant prognostic value of SIRPA, suggesting its potential as a target for immunotherapy. These findings established a framework for using immune checkpoints as prognostic biomarkers, highlighting their important role in enhancing personalized treatment strategies for OS patients.

Additionally, tumour recurrence following ADT was delayed by pharmacological suppression of TDO2-Kyn-AhR signalling with a TDO2 inhibitor or an AhR inhibitor. In summary, we describe a signalling circuit mediated by tryptophan metabolism for regulating tumour cell dormancy and recurrence and propose TDO2 as a new target for the treatment of androgen-sensitive prostate cancer patients in combination with ADT.