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Review
. 2024 Apr 29;25(9):4849.
doi: 10.3390/ijms25094849.

Macrophage Migration Inhibitory Factor (MIF) and D-Dopachrome Tautomerase (DDT): Pathways to Tumorigenesis and Therapeutic Opportunities

Caroline Naomi Valdez  1 , Gabriela Athziri Sánchez-Zuno  2 , Richard Bucala  1   2   3 , Thuy T Tran  1   3   4
Affiliations
Review

Macrophage Migration Inhibitory Factor (MIF) and D-Dopachrome Tautomerase (DDT): Pathways to Tumorigenesis and Therapeutic Opportunities

Caroline Naomi Valdez et al. Int J Mol Sci. .

Abstract

Discovered as inflammatory cytokines, MIF and DDT exhibit widespread expression and have emerged as critical mediators in the response to infection, inflammation, and more recently, in cancer. In this comprehensive review, we provide details on their structures, binding partners, regulatory mechanisms, and roles in cancer. We also elaborate on their significant impact in driving tumorigenesis across various cancer types, supported by extensive in vitro, in vivo, bioinformatic, and clinical studies. To date, only a limited number of clinical trials have explored MIF as a therapeutic target in cancer patients, and DDT has not been evaluated. The ongoing pursuit of optimal strategies for targeting MIF and DDT highlights their potential as promising antitumor candidates. Dual inhibition of MIF and DDT may allow for the most effective suppression of canonical and non-canonical signaling pathways, warranting further investigations and clinical exploration.

Keywords: D-dopachrome tautomerase; DDT; MIF; Macrophage Migratory Inhibition Factor; cancer; cytokines; oncology.

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Conflict of interest statement

R.B. is a co-inventor on Yale-managed patents for therapeutic MIF/DDT antagonism and serves on the Clinical Advisory Board for OncoOne GmbH.

Figures

Figure 1
Figure 1
(a) Molecular models of MIF and DDT tertiary and homotrimeric structures and (b) schematic diagrams of the human MIF and DDT genes. The MIF gene depicts two known promotor polymorphisms: the -794 CATT5–8 short-tandem repeat and -173 G/C single-nucleotide polymorphism. (c) MIF and DDT binding interactions, subsequent canonical (CD74/CD44) and non-canonical (CXCR2, CXCR4, and CXCR7) pathways, and downstream activities implicated in tumorigenesis. In vivo and therapeutic agents tested in preclinical and clinical cancer models (Imalumab, Ibudilast, Milatuzumab, 4-IPP, ISO-1, CPSI-1306, SCD-19, and anti-MIF and anti-DDT antibodies) are shown at their levels of inhibition in red.
Figure 2
Figure 2
Evidence of MIF and DDT dysregulation has been described in a wide range of cancers, including hematologic, musculoskeletal, skin, head and neck, lung, gastrointestinal, CNS, urogenital, and gynecologic cancers.
Figure 3
Figure 3
Modified version of cancer hallmarks, as previously described by Hanahan and Weinberg, with evidence of MIF (*) and DDT (ꝉ) involvement, accompanied by references.
Figure 4
Figure 4
Distributions of MIF (top), DDT (center), and CD74 (bottom) differential expression levels across all TCGA tumors using TIMER 2.0 [52]. Normal (blue), tumor (red), and metastatic (purple) tissues are represented. (Wilcoxon statistical significance *: p-value < 0.05; **: p-value < 0.01; ***: p-value < 0.001).
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Grants and funding

This research was funded by the Head and Neck Cancer SPORE and Skin Cancer SPORE Career Enhancement Program (CEP) (T.T.T.), the Stephen A. Sherwin ’70 MD Translational Research Fellowship Award (T.T.T.), and the William U. Gardner Memorial Student Research Fellowship at Yale University School of Medicine (C.N.V.).

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