We will outline three different strategies that tackle the IDO1/TDO2-Kyn-AhR signaling circuitry in cancer treatment: (i) pharmacological inhibition of IDO1/TDO2 by IDO1 inhibitors, (ii), systemic depletion of Kyn by engineered kynureninase, and (iii) blockade of AhR activation by synthetic AhR modulators (Table 3). Here, TDO2 is linked to cancer.