Microbial influence on tryptophan metabolism in tumors:Mechanisms and potential clinical applications

Tryptophan (Trp) metabolism represents a major biochemical interface between the gut microbiota, host immunity, and tumor biology. Trp is metabolized through three interconnected routes: the kynurenine (Kyn) pathway, mainly regulated by indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase 2 (TDO2); the serotonin/5-hydroxytryptamine (5-HT) pathway; and the microbial indole derivative pathway. These metabolites regulate tumor development through multiple mechanisms, including aryl hydrocarbon receptor (AhR) activation, epithelial barrier modulation, immune checkpoint regulation, tumor-associated macrophage polarization, cytotoxic T-cell dysfunction, and treatment response. Importantly, Trp metabolites may exert either tumor-promoting or tumor-suppressive effects depending on microbial composition, metabolite concentration, receptor usage, immune contexture, tumor type, and therapeutic setting. In this review, we summarize recent advances in host- and microbiota-derived Trp metabolism, discuss mechanistic differences between Kyn-AhR and indole-AhR signaling, and critically evaluate therapeutic strategies targeting IDO1/TDO2, microbial metabolites, probiotics, diet, chemotherapy, and immune checkpoint blockade. We also highlight unresolved issues, including causality in microbiome studies, gut versus intratumoral microbiota, biomarker-guided patient selection, and the context-dependent nature of AhR signaling. Collectively, these findings support the concept that tryptophan metabolism functions as a context-dependent host-microbiota co-regulated network, and that its precise modulation may provide novel opportunities for biomarker-guided and mechanism-based cancer therapy.