This includes targeting the indoleamine 2, 3-dioxygenase with small-molecule inhibitors and engineered enzymes that degrade kynurenine, an immunosuppressive metabolite produced during tryptophan depletion shown to dampen responses to immunotherapy in CRC models.[84,85] Targeting transforming growth factor (TGF) -β is of also particular interest given its role in modulating the balance of T-regs and Th17 cells in the gut.[86] In direct support of this, combining OX40 agonists with a TGFβ inhibitor caused regression of large established tumors in preclinical CRC models.[87]. This evidence concerns the gene TNFRSF4 and colorectal carcinoma.