Prognostic and immunological significance of tryptophan metabolic enzymes across endometrial cancer molecular subtypes

Background The kynurenine pathway is a key immunosuppressive mechanism implicated in resistance to immune checkpoint inhibitors (ICIs). This study investigated expression of tryptophan-metabolising enzymes (IDO1, TDO2, IL4I1) and their relationship with the immune microenvironment across molecular subtypes of endometrial cancer (EC). Methods A cohort of 570 ECs was classified as mismatch repair-deficient (MMRd), p53-mutant (p53mut), or no specific molecular profile (NSMP). Expression of IDO1, TDO2, IL4I1, PD-L1, kynurenine, and immune markers (CD8, FOXP3, CD68, CD163) was assessed by immunohistochemistry and quantified in tumour and stromal compartments using QuPath. Associations with disease-specific survival (DSS) were analysed using correlation testing, Kaplan–Meier, and Cox regression. Results IDO1, TDO2, and IL4I1 correlated strongly with immune infiltrate density. High IDO1 tumour expression was linked to improved DSS in NSMP and p53mut tumours (p < 0.05), consistent with an “inflamed” phenotype. In contrast, high TDO2 stromal expression predicted reduced DSS in NSMP patients (p < 0.05). Elevated IL4I1 tumour expression was associated with improved DSS in MMRd tumours (p < 0.05). A high CD163:CD8 ratio independently predicted worse DSS in p53mut tumours (p < 0.05). Both TDO2 and IL4I1 were highly expressed high-risk tumours, particularly p53mut cases. Conclusions 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.