Macrophage Migration Inhibitory Factor (MIF): A Pleiotropic Target Linking Inflammation and Cancer

1. MIF Background: Structure, Expression Regulation, and Basic Biological Characteristics

Macrophage migration inhibitory factor (MIF), initially named for its ability to inhibit macrophage migration, is now widely recognized as a pleiotropic cytokine with pro-inflammatory and chemotactic properties. It is secreted by various immune and non-immune cells and participates in numerous pathological processes such as inflammation, autoimmunity, and cancer ^[1-3].

A unique aspect of MIF is its role as an endogenous counter-regulator of the anti-inflammatory effects of glucocorticoids ^[3], placing it at the core of immune balance. By binding to receptors such as CD74, CXCR2 and CXCR4, MIF forms a complex signaling network and mediates diverse biological effects ^[4-6].

1.1 MIF Structure and Catalytic Activity

MIF's distinctive molecular feature is its intrinsic keto-enol tautomerase activity, setting it apart from most classical cytokines ^[3]. MIF exists as a trimer, and its active site structure confers catalytic potential, enabling participation in various inflammation-related reactions [1]. Its molecular dynamic characteristics are closely related to its biological activity, holding significant importance for drug design ^[17].

Targeting MIF's enzymatic activity has become a focus of therapeutic research. For example, KRP-6, a potent MIF keto-enol tautomerase inhibitor, can block M1 macrophage polarization and oxidative stress responses ^[16]. Conversely, T-614 (iguratimod), a clinical anti-rheumatic drug, inhibits the MIF trimer allosterically, exhibiting non-competitive kinetic characteristics ^{[1, 3]}. Additionally, MIF-2 also possesses similar catalytic activity; its specific inhibitor 4-CPPC can selectively block MIF-2 binding to CD74, providing a tool for studying family functions ^[10]. These studies reveal that MIF's enzymatic activity and structural features are crucial for its biological roles.

1.2 Expression Regulation and Genetic Variation

MIF expression is regulated at multiple levels, involving transcription, translation, and responses to external stimuli. Pathogen-associated molecular patterns (e.g., LPS) can induce MIF expression, indicating its significant role in innate immunity ^[18].

The transcription factor ICBP90 (UHRF1) regulates MIF transcriptional activity by binding to the −794 CATT repeat sequence in the MIF gene promoter region; the length of this site is significantly associated with MIF expression and glucocorticoid resistance ^[19]. Furthermore, MIF promoter polymorphisms (−173 G/C, −794 CATT) are significantly associated with the risk of diseases like Alzheimer's disease ^[20]. These variants can influence MIF expression efficiency and individual susceptibility to disease ^{[21, 22]}. Understanding its genetic regulatory mechanisms is valuable for elucidating the pathogenesis and drug responses in MIF-related diseases.

1.3 Basic Biological Functions

MIF plays a central role in cell proliferation, migration, and inflammatory responses. Studies show that recombinant MIF can concentration-dependently promote cell proliferation and accelerate the G1/S phase transition in gastric cancer cells ^[23]. The mechanism involves upregulating Cyclin D1, downregulating p27(Kip1), and activating the PI3K/Akt signaling pathway. The PI3K inhibitor LY294002 can completely block these effects ^[23].

These findings indicate that MIF promotes cell proliferation by regulating the PI3K/Akt-Cyclin D1 axis, revealing its key role in tumor development.

1.4 MIF Family Member MIF-2/DDT

MIF-2 (DDT) is the second member of the MIF family, sharing keto-enol tautomerase activity and receptor-binding characteristics with MIF-1 ^[10]. Large-scale compound screening identified 4-CPPC, which selectively inhibits MIF-2 enzymatic activity and blocks its binding to CD74, without affecting MIF-1-CD74 signaling ^[10]. This research highlights the uniqueness of MIF-2 in structure and function, providing a new direction for developing highly selective targeted drugs.

2. MIF Receptors and Signaling Pathways

2.1 MIF Receptors and Interactions

2.1.1 CD74 as a High-Affinity Receptor

CD74, originally identified as an MHC class II chaperone, is also a high-affinity receptor for MIF and can independently mediate various biological functions ^[24]. In activated T cells, CD74 is significantly upregulated and forms a complex with CXCR4, participating in MIF-induced migration ^[4]. In various tumors, the CD74-MIF signal promotes cell proliferation, migration, and therapy resistance via pathways such as ERK and AKT ^{[12, 29, 30]}.

In breast cancer, the AEP-CD74 axis activates ERK signaling to promote EMT, while inhibiting AEP and CD74 significantly reduces metastasis ^[32]. In multiple myeloma, glioblastoma, and others, upregulation of the MIF/CD74 signal is associated with immune escape and therapy tolerance ^[33-35]. Additionally, the MIF/CD74 axis also plays regulatory roles in diseases such as myasthenia gravis and endometriosis ^{[36, 37]}.

2.1.2 Chemotactic Role of CXCR2 and CXCR4

Although MIF lacks a typical chemokine structure, it can bind to CXCR2 and CXCR4 via its N-like loop and pseudo-ELR motif ^[38]. The RLR sequence plays a key role in binding to CXCR4, and its binding mode differs from that of CXCL12 ^[39]. MIF acts as a partial allosteric agonist of CXCR4, modulating non-canonical G protein signaling pathways ^{[38, 40]}.

The MIF-CXCR4 axis promotes cell survival and migration in diseases such as atherosclerosis and neuroblastoma ^[8], and, together with the NFKB2 pathway, participates in drug resistance mechanisms in acute myeloid leukemia ^[41]. Furthermore, sCD74 can induce necroptosis in cardiomyocytes by inhibiting the CXCR4-AKT axis, playing a regulatory role in heart failure ^[14].

Selective inhibition strategies targeting MIF-CXCR4, such as the peptide msR4M-L1, can specifically block this pathway while preserving the protective effects of CXCL12-CXCR4, showing good efficacy in an atherosclerosis model ^[42].

2.2 MIF Downstream Signaling Pathways

MIF regulates cell proliferation, inflammation, metabolism, and immune responses by activating multiple signaling pathways. Major pathways include ERK, JNK, NF-κB, and PI3K/Akt, with downstream effects encompassing cell survival, migration, inflammatory cytokine release, and immune polarization.

2.2.1 Inflammation and Proliferation Signaling

MIF binding to CD74 and its co-receptor CD44 activates the ERK, JNK, and NF-κB pathways ^{[24, 30]}. In thyroid cancer, 4-IPP, which inhibits MIF/CD74 internalization, activates the JNK pathway and induces apoptosis, suggesting the importance of this axis in regulating cell survival and proliferation ^[30].

In a breast cancer metastasis model, AEP enhances epithelial-mesenchymal transition by activating ERK signaling via CD74, while inhibiting AEP and CD74 significantly suppresses cancer cell migration ^[32]. In glioblastoma, the MIF/CD74 signaling inhibitor MN-166 reduces ERK phosphorylation and prolongs patient progression-free survival ^[35]. Additionally, blocking the MIF-CD74 axis can enhance radiotherapy-induced M1 polarization and increase radiosensitivity in a brain metastasis model ^[29].

The NF-κB pathway is also central to MIF-mediated inflammation regulation. Studies show that in FLT3-mutated acute myeloid leukemia, MIF and CXCR2 are upregulated after TKI treatment and activate the non-canonical NFKB2 pathway. Inhibiting NFKB2 significantly downregulates MIF and related inflammatory gene expression ^[41].

Furthermore, the small molecule inhibitor CSB6B can block osteoclast differentiation by promoting MIF degradation and inhibiting NF-κB activation, indicating the role of this pathway in inflammatory bone disease ^[43].

In lung tissue, WISP1 can induce the expression of MIF and its receptors CD74 and CD44, activate EGFR via Src, and initiate multiple pathway signals including NF-κB and PI3K/Akt, promoting the expression of inflammatory factors and remodeling-related molecules, revealing the important regulatory function of the WISP1-MIF axis in airway inflammation ^[31].

Additionally, MIF participates in inflammation amplification and Th17 cell differentiation in rheumatoid arthritis ^[44] and mediates neuroinflammatory responses in chronic pain models ^[45]. In summary, MIF regulates cellular functions through a multi-layered signaling network, forming a pathological loop of inflammation-proliferation-migration.

2.2.2 Metabolic Regulation and Immune Differentiation

MIF is not only an inflammatory mediator but also deeply involved in immunometabolic regulation. In rheumatoid arthritis, MIF promotes Th17 cell differentiation by directly binding to ATF6 and enhancing ATF6 pathway activity, thereby regulating the expression of STAT3 and RORC genes, driving Th17 differentiation, and exacerbating disease progression ^[44].

In the tumor microenvironment, MIF promotes immune escape by influencing macrophage polarization and energy metabolism. For example, in osteosarcoma, increased lactate levels upregulate MIF expression via histone H3K9 lactylation, thereby driving macrophage M2 polarization ^[46]. The combination of the MIF inhibitor 4-IPP and PD-1 antibody significantly inhibits tumor growth, demonstrating potential for synergistic immunotherapy ^[46].

Furthermore, MIF is regulated by the estrogen-GPER pathway; a hypoxic environment can induce upregulation of MIF and HIF-1α, while activating GPER lowers their levels, suggesting a key role for MIF in endocrine stress adaptation ^[47].

2.3 Interactions with Other Molecules

MIF can form heterocomplexes with other chemokines to modulate function. For instance, MIF forms a high-affinity complex with platelet-derived CXCL4L1, blocking MIF-mediated T cell chemotaxis and thrombosis ^[5]. This complex acts as an endogenous inhibitor by interfering with the MIF-CXCR4 binding pathway ^[5].

Additionally, soluble CD74 (sCD74) can synergize with MIF to induce necroptosis in cardiac fibroblasts. Mechanistically, sCD74 impairs MIF-mediated AKT activation, promotes p38 pathway activation, and induces RIP1/RIP3-dependent necrosis. The sCD74/MIF ratio is significantly decreased in the serum of heart failure patients, suggesting potential biomarker significance for this axis ^[14].

These studies indicate that MIF finely tunes signal intensity and directionality through interactions with different molecules, forming the molecular basis of its pleiotropy.

3. Role of MIF in Related Diseases

MIF is widely involved in the pathological processes of tumors, immune, metabolic, and cardiovascular diseases. Its pro-inflammatory and pro-survival properties make it an important regulatory factor in disease progression.

3.1 MIF and Tumor Development

MIF exhibits pro-tumor activity in various cancers.

In gastric cancer, MIF promotes cell proliferation and G1/S transition by upregulating Cyclin D1, downregulating p27, and activating the PI3K/Akt pathway ^[23]. In pancreatic cancer, the MIF inhibitor ISO-1 effectively blocks tumor growth and inhibits cell migration and invasion ^[48]. In hepatocellular carcinoma, MIF inhibition is associated with mTOR pathway regulation ^[27].

MIF also plays a key role in tumor invasion and metastasis. In neuroblastoma, the bone marrow microenvironment induces CXCR4 upregulation, enhancing MIF signaling and PI3K/AKT and ERK activity; inhibiting MIF delays tumor progression and increases chemotherapy sensitivity ^[8]. In breast cancer, the AEP-CD74-ERK pathway promotes EMT, and inhibiting this axis significantly suppresses metastasis ^[32].

In osteosarcoma, lactate enhances MIF transcription via histone lactylation, driving macrophage M2 polarization; combined treatment with a MIF inhibitor and PD-1 antibody enhances anti-tumor immunity ^[46]. The MIF/CXCR4 axis promotes macrophage polarization in GIST and is associated with recurrence risk ^[7].

MIF, together with the HIF and NF-κB/IL-6 axes, promotes myeloid cell recruitment and angiogenesis in non-small cell lung cancer brain metastasis and head and neck squamous cell carcinoma ^{[6, 29]}.

Furthermore, MIF/CD74 signaling is upregulated in thyroid cancer, melanoma, and multiple myeloma, closely associated with cell survival, therapy resistance, and immune escape ^{[28, 30, 33, 34]}.

In clinical applications, serum MIF levels are associated with prognosis in some tumors. Elevated pre-treatment MIF levels in osteosarcoma patients are associated with poorer efficacy, while a post-treatment decrease suggests improved prognosis ^[51]. However, its efficacy as a standalone biomarker in lung cancer is limited ^[25].

These studies demonstrate that MIF systemically promotes tumor development by regulating cell proliferation, migration, and the immune microenvironment, potentially serving as a universal therapeutic target across multiple cancer types.

3.2 Inflammatory and Autoimmune Diseases

MIF is a potent pro-inflammatory factor, upregulated in diseases such as rheumatoid arthritis, asthma, and myasthenia gravis ^{[1, 15, 37]}. In RA, MIF promotes Th17 differentiation and exacerbates inflammation ^[44]; in an allergic asthma model, the MIF inhibitor SCD-19 effectively alleviates airway inflammation and tissue remodeling ^[15]; in myasthenia gravis, MIF-CD74 signaling enhances B cell survival and positively correlates with disease severity ^[37].

MIF is also involved in acute liver injury, chronic kidney disease, and TAA-induced nephrotoxicity, manifested as enhanced oxidative stress and pro-fibrotic responses ^{[1, 2, 11]}. Its inhibitor, iguratimod, significantly improves survival rates and reduces oxidative stress in liver injury models ^[3].

In neurodegenerative diseases, MIF secreted by peripheral immune cells can exacerbate Alzheimer's disease pathology via CD74-CD44 signaling ^[13]. In the cardiovascular system, a decreased sCD74/MIF ratio is associated with heart failure progression ^[14]. These results indicate that MIF plays a central driving role in multi-system inflammation and immunopathology.

4. Research Progress on MIF as a Drug Target

Macrophage migration inhibitory factor (MIF), as an important target for inflammation and immune regulation, is seeing diversified trends in related drug research and development. Current investigational drugs include small molecule chemicals, antibodies, PROTACs, gene therapies, and other types, with mechanisms covering MIF inhibition, CD74 inhibition, oxMIF targeting, etc. These drugs are being explored extensively in fields such as oncology, inflammatory diseases, neurodegenerative diseases, and fibrosis. Multiple institutions globally are involved in R&D, with most projects in the preclinical stage. Only ibudilast has been approved for marketing, marking the progression of drug development for this target from basic research towards clinical translation.

Drug Name	Mechanism of Action	Drug Type	Investigated Indications	Research Institution(s)	Highest Phase
Ibudilast	MIF inhibitor \| PDE10A inhibitor \| PDE11A inhibitor \| PDE3 inhibitor \| PDE4 inhibitor \| TLR4 antagonist	Small Molecule Chemical Drug	Asthma \| Cerebral Hemorrhage \| Cervical Spondylotic Myelopathy \| Amyotrophic Lateral Sclerosis \| Post-COVID-19 Sequelae, etc.	KYORIN Pharmaceutical Co., Ltd. \| The Ohio State University \| MediciNova, Inc. \| University of Pennsylvania \| Portland VA Medical Center	Approved
Imalumab	MIF inhibitor \| Immunomodulator	Monoclonal Antibody	Ascites \| Colorectal Cancer	Cytokine PharmaSciences, Inc.	Phase 2
IPG-1094	MIF Inhibitor	Small Molecule Chemical Drug	Lupus Nephritis \| Locally Advanced Malignant Solid Tumors \| Melanoma \| Lung Cancer Brain Metastasis \| Inflammatory Bowel Disease	Nanjing Aimeiqi Biopharmaceutical Technology Co., Ltd.	Phase 2
Fibrosis(Apaxen)	MIF Inhibitor	Chemical Drug	Fibrosis	Apaxen SA	Preclinical
4-IPP	MIF Inhibitor	Small Molecule Chemical Drug	Acute Myeloid Leukemia	Centre Hospitalier Universitaire Vaudois	Preclinical
MFC-1040	MIF inhibitor \| NLRP3 inhibitor	Small Molecule Chemical Drug	Asthma \| Idiopathic Pulmonary Fibrosis \| Pulmonary Arterial Hypertension	Sorbonne Paris Cité \| Apaxen SA \| Institut National de la Santé et de la Recherche Médicale \| Université Paris-Saclay \| Assistance Publique des Hôpitaux de Paris SA \| Mifcare	Preclinical
INV-88	MIF Inhibitor	Small Molecule Chemical Drug	Tumors \| Neurological Diseases \| Fibrosis \| Hematologic Tumors \| Rheumatoid Arthritis \| Solid Tumors	Innovimmune Biotherapeutics, Inc.	Preclinical
RGB097	MIF Inhibitor	Small Molecule Chemical Drug	Tumors	University of Groningen	Preclinical
Zr89-ON102	MIF Inhibitor	Diagnostic Radiopharmaceutical	Solid Tumors	OncoOne Research & Development GmbH	Preclinical
THOR-213	CD74 inhibitor \| MIF inhibitor	ASO	Cachexia	Thor Therapeutics Inc.	Preclinical
Hit-1(WuXi AppTec )	MIF Inhibitor	Small Molecule Chemical Drug	Sepsis	WuXi AppTec Co., Ltd. \| Nanjing Medical University	Preclinical
MD13	MIF Degrader \| Protein Degradation	Protein Hydrolysis-Targeting Chimera (PROTAC)	Lung Cancer	University of Groningen	Preclinical
Compound 37 (University of Pecs)	MIF Inhibitor	Small Molecule Chemical Drug	Septic Shock	University of Pecs	Preclinical
ON05+Lu177-di-HSG	Histamine succinyl glycine inhibitor \| MFN2 regulator \| oxMIF inhibitor	Bispecific Antibody \| Therapeutic Radiopharmaceutical	Colorectal Cancer \| Head and Neck Cancer \| Pancreatic Cancer \| Gastric Cancer	OncoOne Research & Development GmbH	Preclinical
ISO-1	MIF Inhibitor	Small Molecule Chemical Drug	Prostatitis \| Disc Degeneration \| Myositis \| Ross River Fever	Soochow University \| University of Canberra \| Griffith University \| Anhui Medical University \| Jiangsu University	Preclinical
MIF-PROTAC(Princess Máxima Center)	MIF Degrader	Protein Hydrolysis-Targeting Chimera (PROTAC)	Neuroblastoma	Prinses Máxima Centrum voor Kinderoncologie BV	Preclinical
PAANIB-1	MIF Inhibitor	Chemical Drug	Parkinson's Disease	The Johns Hopkins University	Preclinical
ON-102	oxMIF Inhibitor	Diagnostic Radiopharmaceutical	Inflammation \| Solid Tumors	OncoOne Research & Development GmbH	Preclinical
P-EHC	MIF Inhibitor	Chemical Drug	Ischemia \| Reperfusion Injury	China Pharmaceutical University	Preclinical
ON-203	oxMIF Inhibitor	Monoclonal Antibody	Colorectal Cancer \| Lung Cancer	OncoOne Research & Development GmbH	Preclinical
Napa-001(NapaJen Pharma)	MIF Inhibitor	Oligonucleotide	Ulcerative Colitis \| Rheumatoid Arthritis	NapaJen Pharma, Inc.	Preclinical
ON-104	oxMIF Inhibitor	Monoclonal Antibody	Nephritis \| Asthma \| Inflammatory Bowel Disease \| Rheumatoid Arthritis	OncoOne Research & Development GmbH	Preclinical
DRalpha1-hMOG-35-55 (Virogenomics Biodevelopment)	CD74 inhibitor \| HLA class II antigen modulator \| MIF inhibitor	Recombinant Protein	Multiple Sclerosis	Virogenomics, Inc.	Preclinical
MFC-2040	MIF Inhibitor	Small Molecule Chemical Drug	Pulmonary Arterial Hypertension	Mifcare	Preclinical
PAV-174	MIF Inhibitor	Small Molecule Chemical Drug	Alzheimer's Disease	Prosetta Biosciences, Inc.	Preclinical
AAV-PHP.eB-MIF-HA	MIF Inhibitor	AAV Gene Therapy	Amyotrophic Lateral Sclerosis	-	Preclinical
M1	MIF Inhibitor	Monoclonal Antibody	Inflammation	Zavod Republike Slovenije ZA Transfuzijsko Medicino	Preclinical

(Data as of November 8, 2025, source: synapse)

5. MIF Research Tools

Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine that plays a key role in inflammation, autoimmune diseases, malignant tumors, and multi-organ injury. Its unique glucocorticoid counter-regulatory property makes it an important molecular target for inflammation and immune regulation. Huamei Bio provides MIF recombinant proteins, antibodies, and ELISA kits to support your related mechanism research and targeted drug development.

● MIF Recombinant Protein

Recombinant Human Macrophage migration inhibitory factor (MIF) (Active); CSB-MP013826HU

● MIF Antibodies

MIF Recombinant Monoclonal Antibody; CSB-RA146975A0HU

MIF Recombinant Monoclonal Antibody; CSB-RA013826MA1HU

MIF Antibody; CSB-PA06867A0Rb

● MIF ELISA Kit

Human Macrophage Migration Inhibitory Factor,MIF ELISA Kit

CSB-E08330h

Rat Macrophage Migration Inhibitory Factor,MIF ELISA Kit

CSB-E07293r

Mouse Macrophage Migration Inhibitory Factor,MIF ELISA Kit

CSB-E07292m

References

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[24] R. Lindner.(2017). Invariant Chain Complexes and Clusters as Platforms for MIF Signaling.

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