Identification of IDO1 depedent genes upon IFN-γ stimulation

A key mechanism of malignant cell evasion from anti-tumor immunity centers on tryptophan metabolism by indole-2,3-dioxygenase (IDO1). By degrading tryptophan, IDO1 impairs anti-tumor T cell responses, which should be restored by IDO1 inhibitors (IDO1i). All IDO1i have, however, failed their clinical trials. Therefore, we sought to further investigate the cell intrisic biological function of IDO1 in the context of ovarian cancer by combining spatial proteomics and bulk RNA sequencing. We discovered that IFN-γ killed ovarian cancer cells via a linear pathway that required IFN-γ signaling, IDO1, tryptophan depletion followed by a duality of effects of the integrated stress response that initially protect against tryptophan depletion and later initiate cell death, potentially accounting for the heterogenous expression on IDO1 in situ. By contrast, IDO1i rescued these effects and promoted cancer cell survival. In summary, our results uncover a new facet of IDO1 biology in cancer and suggest that further investigation is required to justify IDO1i use in clinics.