Revisiting tryptophan metabolism in cancer: complexity, context, and spatial heterogeneity

Tryptophan (TRP) metabolism has long been associated with cancer immunity, primarily through the kynurenine pathway mediated by indoleamine-2,3-dioxygenase 1 (IDO1) and tryptophan-2,3-dioxygenase (TDO2). Both enzymes can deplete TRP within cells and in local microenvironments, triggering dysfunction of T cells with anti-tumor functions. This view fostered the development of IDO1/TDO2 inhibitors, which ultimately failed in clinical trials. However, we now know that TRP metabolism in tumors is far more complex than anticipated. Recent work highlights the dual, context-dependent roles of TRP-depleting enzymes. Importantly, advances in spatial profiling have uncovered that TRP-metabolizing enzymes are not uniformly expressed but instead form distinct metabolic niches within tumors. 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.