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

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‑γ (IFN‑γ) signaling and heterogeneously expressed. Across orthogonal models with tunable IDO1, IFN‑γ killed ovarian cancer via a pathway requiring IFN‑γ 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.