In addition, PGE2, a molecule derived from cyclo-oxygenase-1/2 (COX1/2) activity, drives IDO1 and TDO2 expression and activity in human cancer cells through activation of EP4.35,167 COX2 is induced in response to inflammatory stimuli, which are present in the tumour microenvironment168,169 and enriched upon treatment with immune checkpoint blockade alone164,165 and also in combination with IDO1 inhibition.21 Therefore, activation of the COX2–PGE2–EP4 pathway may have increased IDO1 and TDO2 levels possibly rendering IDO1 inhibitors unable to inhibit Trp degradation (Fig. 2c). Here, TDO2 is linked to cancer.