AbstractBackgroundMetabolites of tryptophan (Trp) metabolism in the tumor microenvironment play crucial immunosuppressive roles in various cancers. However, the role of Trp metabolism in diffuse large B‐cell lymphoma (DLBCL) or natural killer/T‐cell lymphoma (NK/TCL) remains unelucidated.MethodsWe investigated the potential role of Trp metabolism in a cohort of 43 patients with DLBCL and 23 with NK/TCL. We constructed tissue microarrays and performed in situ staining of Trp‐catabolizing enzymes and PD‐L1 using immunohistochemistry (IHC).ResultsWe observed 14.0% positive staining of IDO1 in DCBCL and 60.9% in NK/TCL; 55.8% of IDO2 in DCBCL and 95.7% in NK/TCL; 79.1% of TDO2 in DCBCL and 43.5% in NK/TCL; 29.7% of IL4I1 in DCBCL and 39.1% in NK/TCL. However, IDO1, IDO2, TDO2, and IL4I1 positivity did not significantly differ between PD‐L1+ and PD‐L1− biopsy tissue samples of NK/TCL; nonetheless, a positive correlation of IDO1 (r= 0.87,p< 0.001), IDO2 (r= 0.70,p< 0.001), TDO2 (r= 0.63,p< 0.001), and IL4I1 (r= 0.53,p< 0.05) with PD‐L1 expression was observed in the TCGA‐DLBCL dataset. Finally, immunohistochemical (IHC) analysis revealed the lack of superior prognostic effect with higher expression of Trp enzymes in DLBCL and NK/TCL. Furthermore, IDO1, IDO2, TDO2, and IL4I1 expression, as well as survival rates, did not significantly differ across all groups in the TCGA‐DLBCL cohort.ConclusionCollectively, our findings provide novel insights into the enzymes involved in Trp metabolism in DLBCL and NK/TCL and their association with PD‐L1 expression, which offers potential strategies to combine Trp‐metabolism enzyme inhibitors with anti‐PD‐L1 or other immunotherapeutic strategies in clinical DLBCL or NK/TCL treatment.