Fig. 7

A Dual role of IDO1/TDO2 in KYN-mediated cisplatin-resistance. (1) Inhibition of IDO1 results in compensatory TDO2 expression for that loss of function. (2) Dual IDO1/TDO2 inhibition (AT-0174) is crucial for the inhibition of KYN in CR cells. (3) Reduced KYN (a potent inhibitor of ferroptosis?) leads to increase ROS and lipid peroxidation. (4) Suppressing KYN production reverses the immunosuppressive environment by enhancing NKG2D on NK and CD8 + T cells and suppressing Tregs. (5) AT-0174 + PD-1 blockade further enhances anti-tumor immunity in platinum-resistant NSCLC. B CR cells undergo metabolic reprogramming wherein tumors become more reliant on oxidative metabolism (OXMET). TRP can be substituted for serine as a one-carbon donor [49]. We postulate that the depletion of glycolytic-derived serine will hypersensitize CR tumors to IDO1/TDO2 inhibition