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

Xu, T. T.; Metousis, A.; Kainacher, L.; Zhang, X.; Steigenberger, B.; Madden, K. G.; Schweitzer, L. C.; Duteil, C.; Rossini, S.; Lengyel, E.; Obermayr, E.; Shulman, Z.; Nordmann, T. M.; Lindberg, E. L.; Mann, M.; Murray, P. J.

doi:10.1101/2025.08.14.670277

bioRxiv · 10.1101/2025.08.14.670277

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

Xu, T. T.·Metousis, A.·Kainacher, L.·Zhang, X.·Steigenberger, B.·Madden, K. G.·Schweitzer, L. C.·Duteil, C.·Rossini, S.·Lengyel, E.·Obermayr, E.·Shulman, Z.·Nordmann, T. M.·Lindberg, E. L.·Mann, M.·Murray, P. J.

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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.

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Xu, T. T., Metousis, A., Kainacher, L., Zhang, X., Steigenberger, B., Madden, K. G., Schweitzer, L. C., Duteil, C., Rossini, S., Lengyel, E., Obermayr, E., Shulman, Z., Nordmann, T. M., Lindberg, E. L., Mann, M., Murray, P. J.. 2025-08-18. Spatial proteomics reveals mechanisms of cell-intrinsic tryptophan metabolism controlling ovarian cancer survival. https://doi.org/10.1101/2025.08.14.670277

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