Targeting tryptophan metabolism in breast cancer immunotherapy: Recent advances and future prospects

Breast cancer (BC), a leading cause of cancer-related mortality in women, is predominantly characterized as an immunologically "cold" malignancy. This recalcitrant nature is largely attributed to its profound metabolic landscape, which orchestrates a hostile tumor microenvironment (TME). Central to this metabolic subversion is the kynurenine (Kyn) pathway of tryptophan (Trp) catabolism. Driven by the rate-limiting enzymes indoleamine 2,3-dioxygenase 1/2 (IDO1/2) and tryptophan 2,3-dioxygenase (TDO2), this axis functions as a critical molecular rheostat that promotes immune evasion by depleting essential Trp and accumulating bioactive Kyn metabolites. This review provides a comprehensive analysis of the molecular basis by which the Trp-Kyn-aryl hydrocarbon receptor (AhR) signaling axis impairs T-cell effector function, induces regulatory T-cell (Treg) differentiation, and modulates the plasticity of myeloid-derived suppressor cells (MDSCs) specifically within the BC context. We critically evaluate the clinical trajectory of first-generation IDO1 inhibitors, analyzing the biochemical and compensatory mechanisms-such as TDO2 upregulation-that contributed to recent clinical setbacks. Furthermore, we highlight emerging strategies, including dual IDO1/TDO2 inhibitors, AhR antagonists, and nanomedicine-based delivery systems designed to overcome metabolic barriers. By emphasizing the integration of Trp-targeted agents with immune checkpoint blockade and other conventional therapies, we propose a framework for biomarker-driven patient stratification. Ultimately, we outline future directions to transition from "one-size-fits-all" approaches toward precision metabolic immunotherapy to unlock robust anti-tumor immunity in breast cancer.