Spatial proteomics reveals mechanisms of cell-intrinsic tryptophan metabolism controlling ovarian cancer survival

Abstract

Indole-2,3-dioxygenase (IDO1) depletes tryptophan to dampen anti-tumor T cells, yet IDO1 inhibitors (IDO1i) have failed clinically. Using deep visual proteomics, we isolated IDO1 high, medium and low ovarian tumor cells in situ and found IDO1 tightly linked to interferon-{gamma} (IFN-{gamma}) signaling and heterogeneously expressed. Across orthogonal models with tunable IDO1, IFN-{gamma} killed ovarian cancer via a pathway requiring IFN-{gamma} signaling, IDO1-dependent tryptophan depletion, and a biphasic integrated stress response that initially protects from starvation and later drives death. IDO1i or tryptophan supplementation rescued these effects, promoting tumor survival. These data reveal a context-dependent, tumor-suppressive facet of IDO1 and explain how IDO1i can paradoxically favor cancer viability. Our findings call for re-evaluation of IDO1 as a target and suggest exploiting the tryptophan-starvation/GCN2-ISR axis to enhance therapy.