Attenuation of tryptophan metabolism by Fe chelators: A hypothesis regarding inhibiting tumor suppressive microenvironments in pancreatic ductal adenocarcinoma

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers. Although extensive research has been conducted on chemotherapy and immunotherapy for PDAC patients, the efficacy of these treatments varies, partially due to immunosuppressive environments and the limited infiltration of effector cells into tumors. Here, we highlight the potential application of iron (Fe) chelators to inhibit immunosuppressive environments in PDAC. This assumption is based on data from published articles indicating that 1) tryptophan (TRP) plays a role in immunosuppressive microenvironments; 2) metabolism of TRP is regulated by tryptophan hydroxylase (TPH), indoleamine-2,3-dioxygenase (IDO), and tryptophan-2,3-doxygenase (TDO), all of which are Fe-dependent enzymes; and 3) wide varieties of both synthetic Fe chelators and natural products are available for clinical application. In light of these data from the literature, we hypothesize that combining Fe chelators with immunotherapeutic or chemotherapeutic agents in PDAC patients can improve treatment efficacy by inhibiting tryptophan depletion in the surrounding mesenchymal stromal cells, allowing effector cells to infiltrate the tumor, and enabling cytotoxic drugs to access the targeted cells.