Indoleamine 2,3-Dioxygenase 1: A Promising Therapeutic Target in Malignant Tumor

Abstract

Tumorigenesis is a complex multifactorial and multistep process in which tumors can utilize a diverse repertoire of immunosuppressive mechanisms to evade host immune attacks. The degradation of tryptophan into immunosuppressive kynurenine is considered an important immunosuppressive mechanism in the tumor microenvironment. There are three enzymes, namely, tryptophan 2,3-dioxygenase (TDO), indoleamine 2,3-dioxygenase 1 (IDO1), and indoleamine 2,3-dioxygenase 2 (IDO2), involved in the metabolism of tryptophan. IDO1 has a wider distribution and higher activity in catalyzing tryptophan than the other two; therefore, it has been studied most extensively. IDO1 is a cytosolic monomeric, heme-containing enzyme, which is now considered an authentic immune regulator and represents one of the promising drug targets for tumor immunotherapy. Collectively, this review highlights the regulation of IDO1 gene expression and the ambivalent mechanisms of IDO1 on the antitumoral immune response. Further, new therapeutic targets via the regulation of IDO1 are discussed. A comprehensive analysis of the expression and biological function of IDO1 can help us to understand the therapeutic strategies of the inhibitors targeting IDO1 in malignant tumors.

Thymol targeting interleukin 4 induced 1 expression reshapes the immune microenvironment to sensitize the immunotherapy in lung adenocarcinoma

“…Indoleamine 2,3‐dioxygenase 1 (IDO1), IDO2, and tryptophan 2,3‐dioxygenase are the main Trp catabolic enzymes. IDO1, which is highly expressed in tumors and associated with resistance to ICBs, has been considered as a promising target for cancer therapy 13,14 . However, increasing evidence shows that cancer patients cannot benefit from the treatment of IDO1 inhibitors alone or in combination with ICBs 15 …”

“…IDO1, which is highly expressed in tumors and associated with resistance to ICBs, has been considered as a promising target for cancer therapy. 13,14 However, increasing evidence shows that cancer patients cannot benefit from the treatment of IDO1 inhibitors alone or in combination with ICBs. 15 A recent study has pointed out that instead of IDO1, interleukin 4 induced 1 (IL4I1) is the novel and the main Trp-catabolic enzyme in glioma and chronic lymphocytic leukemia, which explains the major reason why the clinical trials of IDO1 inhibitors are a failure.…”

Critical Assessment of a Structure-Based Screening Campaign for IDO1 Inhibitors: Tips and Pitfalls

“…Over the past two decades, researchers have paid close attention to IDO1 as a drug target involved in the molecular mechanisms of tumor immune escape [ 14 , 15 , 16 ]. This has fostered the design of catalytic inhibitors of IDO1 ( 7 – 14 ; Figure 2 ) for the development of immunotherapeutic drugs that make tumor cells more vulnerable to T cell detection and destruction [ 17 , 18 ].…”

Role of histone methyltransferase SETDB1 in regulation of tumourigenesis and immune response

“…To date, 18 immune checkpoint inhibitors (ICIs) have been approved as cancer therapeutics, including 12 programmed cell death protein 1 (PD-1) monoclonal antibodies (pembrolizumab, nivolumab, cemiplimab, toripalimab, sintilimab, camrelizumab, tislelizumab, zimberelimab, penpulimab, dostarlimab, serplulimab and prolgolimab), five programmed cell death ligand 1 (PD-L1) monoclonal antibodies (atezolizumab, durvalumab, avelumab, envafolimab and sugemalimab), and one monoclonal antibody that blocks cytotoxic T-lymphocyte associated protein 4 (ipilimumab) ( Dhillon, 2021 ; Dhillon and Duggan, 2022 ; Lee, 2022 ; Markham, 2022 ; Yi et al, 2022 ). Despite considerable advancements, the response rate to ICIs is currently limited to 10%–25% in most tumour types ( Schoenfeld and Hellmann, 2020 ), and those with deficient immunogenic epitopes (low mutational burden) ( Verdegaal et al, 2016 ; Tran et al, 2017 ), impoverished tumour-infiltrating lymphocytes ( Galluzzi et al, 2018 ; Fanale et al, 2022 ), or profuse immunosuppressive factors (such as PD-L1, CD73, and indoleamine 2,3-dioxygenase 1) ( Young et al, 2016 ; Chen and Mellman, 2017 ; Song et al, 2021 ) are less likely to respond ( Galluzzi et al, 2018 ). Furthermore, initial ICI responders may develop acquired resistance ( Schoenfeld and Hellmann, 2020 ).…”