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Leukemia inhibitory factor

Leukemia inhibitory factor (LIF) is a pleiotropic cytokine in the interleukin-6 (IL-6) family, initially identified in 1987 for its ability to induce terminal differentiation and inhibit the proliferation of murine myeloid leukemia M1 cells, from which it derives its name.^[1] It exists as a glycoprotein of 38–67 kDa (unglycosylated core ~20 kDa) derived from a 202-amino-acid precursor, featuring a characteristic four-helix bundle structure stabilized by three disulfide bonds.^[1]^[2] LIF signals through a heterodimeric receptor complex composed of the LIF receptor β (LIFRβ) and the shared glycoprotein 130 (gp130) subunit, with high affinity (Kd = 50–100 pM), leading to activation of downstream pathways including Janus kinase/signal transducer and activator of transcription (JAK/STAT, particularly STAT3), mitogen-activated protein kinase (MAPK), and phosphoinositide 3-kinase (PI3K/AKT).^[1] Expressed in nearly all tissues, LIF exerts diverse effects on cell proliferation, differentiation, survival, and inflammation, often in a context-dependent manner.^[3] In reproduction, LIF plays a critical role in blastocyst implantation by promoting uterine epithelial receptivity and stromal decidualization; knockout studies in mice demonstrate infertility due to implantation failure, and reduced LIF levels in human endometrial fluid correlate with infertility.^[1] In hematopoiesis, it synergizes with factors like IL-3 to support hematopoietic stem cell self-renewal and blast cell proliferation while maintaining pluripotency in embryonic stem cells.^[1] Neurologically, LIF promotes sensory neuron survival, differentiation, myelination, and repair following injury, contributing to neuroprotection in conditions like ischemia.^[1] Additionally, it modulates inflammatory responses, exhibiting both pro-inflammatory effects (e.g., enhancing neutrophil adhesion and cytokine production) and anti-inflammatory actions (e.g., suppressing lipopolysaccharide-induced responses).^[3] LIF's role in pathology is multifaceted, particularly in cancer, where it acts as a "double-edged sword": it inhibits myeloid leukemia growth but promotes oncogenesis in solid tumors such as breast, colorectal, and pancreatic cancers by enhancing cancer stem cell maintenance, metastasis, immunosuppression (via tumor-associated macrophages and regulatory T cells), and metabolic reprogramming like the Warburg effect.^[4] Elevated serum LIF levels often correlate with poor prognosis and chemoresistance in these malignancies, mediated primarily through STAT3 activation.^[4] Therapeutically, recombinant LIF has been explored for stimulating hematopoiesis and treating neuropathy, while LIF-neutralizing antibodies (e.g., MSC-1) and small-molecule LIFR inhibitors (e.g., EC359) show promise in blocking tumor progression and enhancing immunotherapy efficacy, with ongoing clinical trials evaluating safety and antitumor effects.^[4]

Discovery and molecular properties

Historical discovery

Leukemia inhibitory factor (LIF) was first discovered in 1987 through studies on conditioned medium derived from Krebs II ascites tumor cells, where it was identified as a soluble factor that suppressed the differentiation of murine myeloid leukemia M1 cells while promoting their self-renewal and inhibiting proliferation.^[5] This activity was initially termed "differentiation inhibitory activity" (DIA) based on its effects in leukemia cell lines.^[1] Purification efforts in 1988, led by researchers at the Walter and Eliza Hall Institute including Tony Burgess, Nick Nicola, David Gearing, and Nicholas Gough, isolated the glycoprotein from Krebs II cell medium and determined its partial amino acid sequence using techniques like high-performance liquid chromatography and Edman degradation.^[6] The team had cloned the cDNA encoding murine LIF in 1987, enabling recombinant expression and confirmation of its biological activity on M1 cells.^[5] Human LIF was similarly cloned in 1988 by Metcalf and colleagues, revealing high sequence conservation between species. The factor was officially named leukemia inhibitory factor (LIF) to highlight its role in inducing terminal differentiation and thereby inhibiting growth in myeloid leukemia cells.^[1] By 1990, sequence analysis and structural predictions identified LIF as the third member of the interleukin-6 (IL-6) cytokine family, following IL-6 and oncostatin M, due to shared four-helix bundle topology and homology in key functional domains.^[7] Early functional studies in the 1990s further elucidated LIF's broader roles beyond leukemia cells.

Gene and protein characteristics

The human LIF gene is located on the long arm of chromosome 22 at position 22q12.2 and spans approximately 6.3 kb, consisting of three exons interrupted by two introns.^[8]^[9] The orthologous Lif gene in mice resides on chromosome 11 and exhibits a similar genomic organization with three exons.^[10]^[9] The LIF gene encodes a precursor protein of 202 amino acids, which undergoes cleavage of a 22-amino-acid N-terminal signal peptide to yield the mature form comprising 180 amino acids.^[11] The mature protein is heavily glycosylated, primarily through N-linked modifications at up to six sites, resulting in a molecular weight of approximately 45 kDa despite a calculated unglycosylated mass of about 20 kDa.^[11]^[9] Structurally, LIF adopts a compact four-helix bundle topology characteristic of the interleukin-6 (IL-6) cytokine family, arranged in an up-up-down-down configuration with α-helices A through D connected by loops. Unlike the receptors of this family, which feature a conserved four-cysteine motif and WSXWS sequence in their extracellular domains, the LIF cytokine itself lacks these motifs, relying instead on hydrophobic core interactions within the helical bundle for stability. Sequence conservation between human and mouse LIF is high, with approximately 78% amino acid identity in the mature protein, which supports cross-species biological activity in certain experimental contexts.^[11]

Receptor binding and signaling

Receptor complex formation

Leukemia inhibitory factor (LIF) engages its receptor through a sequential binding mechanism involving a heterodimeric complex composed of the LIF receptor β subunit (LIFRβ, also known as gp190), a type I cytokine receptor, and the shared signal-transducing β subunit gp130. The process initiates with low-affinity binding of LIF to LIFRβ alone, characterized by a dissociation constant (Kd) of approximately 1 nM. This interaction positions LIF to subsequently recruit gp130, forming the high-affinity ternary complex with a Kd of roughly 50–100 pM, which is essential for effective signaling initiation.^[12]^[1] The binding interface on LIF for LIFRβ primarily encompasses the helix A and helix D regions, where critical residues such as Phe156 and Lys159 in human LIF contribute to the specific interaction with the cytokine-binding domain of LIFRβ. These structural elements ensure precise recognition and stabilize the initial low-affinity complex, facilitating the subsequent conformational changes necessary for gp130 association. Crystallographic analysis has revealed that the ectodomain of LIFRβ interacts with LIF via an immunoglobulin-like domain, enhancing the specificity of this binding step.^[13]^[14] Expression of the receptor components exhibits distinct patterns: gp130 is ubiquitously distributed across cell types, enabling broad responsiveness to multiple cytokines, while LIFRβ displays more restricted expression, particularly in embryonic stem cells, neurons, and certain trophoblast cells. This differential expression limits LIF responsiveness to specific tissues and developmental contexts. The functional receptor complex assembles into a 1:1:1 stoichiometry of LIF:LIFRβ:gp130, forming a trimeric structure that promotes signal transduction, as confirmed by crystallographic studies including the 2003 structure of the binary LIF/gp130 complex and subsequent analyses of the full ternary assembly.^[15]^[16]^[17]

Downstream signaling pathways

Upon engagement of the leukemia inhibitory factor (LIF) receptor complex, the primary downstream signaling cascade is the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway. Receptor-associated JAK1 and JAK2 kinases are activated, leading to phosphorylation of STAT3 at tyrosine 705 (Tyr705). This modification enables STAT3 dimerization, nuclear translocation, and subsequent transcription of target genes, including Sox2 and Nanog.^[18] LIF also triggers secondary pathways, such as the mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) cascade via the Ras-Raf module, which supports proliferative responses. Additionally, the phosphoinositide 3-kinase (PI3K)-Akt pathway is activated, promoting cell survival through downstream effectors like mTOR. The tyrosine phosphatase SHP-2 contributes to pathway modulation by facilitating MAPK/ERK activation while attenuating STAT3 signaling. Negative feedback is mediated by suppressor of cytokine signaling 3 (SOCS3), which is transcriptionally induced by activated STAT3 and binds to JAKs to inhibit their kinase activity. Pathway outcomes can vary by context, with STAT3 signaling often dominating for transcriptional regulation and MAPK/ERK for alternative cellular effects. LIF signaling exhibits cross-talk with other cascades, including integration with Wnt/β-catenin to influence nuclear β-catenin activity. It also intersects with the Hippo/YAP pathway, where YAP/TAZ can mediate aspects of LIF responses through regulation of shared transcriptional targets.

Expression and regulation

Patterns of expression

Leukemia inhibitory factor (LIF) is constitutively expressed at low basal levels in multiple tissues and shows higher expression in immune cells such as monocytes and macrophages, as well as in endometrial glands.^[3] LIF expression is induced under specific conditions, notably during the acute phase response where it is upregulated in hepatocytes by stimuli such as interleukin-1 (IL-1) and lipopolysaccharide (LPS). In the reproductive system, LIF is upregulated in the uterus during the implantation window, specifically on days 4–5 post-fertilization in mice.^[19]^[20] During development, LIF exhibits distinct temporal patterns, with peak expression in the early embryo, particularly in the trophectoderm, and in the placenta, followed by a decline after implantation.^[21]^[22] Expression patterns of LIF are largely similar between humans and mice; however, human LIF shows reduced activity in maintaining mouse embryonic stem cells unless adapted.^[23]

Factors regulating expression

The expression of leukemia inhibitory factor (LIF) is tightly controlled at multiple levels, including transcriptional and post-transcriptional mechanisms, to respond to physiological and pathological cues such as inflammation and hormonal signals.^[24] Transcriptional regulation of LIF involves promoter elements responsive to key transcription factors activated during inflammation and acute phase responses. The LIF promoter contains binding sites for NF-κB, which is activated by pro-inflammatory stimuli like cytokines, leading to upregulated LIF transcription in immune and epithelial cells.^[24] Similarly, C/EBP family members, particularly C/EBPβ, bind to the LIF promoter to drive expression during acute phase reactions in the liver and other tissues, coordinating LIF with other inflammatory mediators.^[24] In reproductive tissues, estrogen and progesterone modulate LIF expression in the endometrium through estrogen receptor (ER) and progesterone receptor (PR) pathways; estrogen induces LIF via ERα in epithelial cells during the proliferative phase.^[1] Post-transcriptional control further fine-tunes LIF levels, with microRNAs influencing mRNA stability and translation. For instance, miR-181a targets the 3'-untranslated region of LIF mRNA, reducing its stability and expression, particularly in contexts like embryo implantation where balanced LIF is critical.^[25] Protein secretion of LIF is also enhanced by pro-inflammatory cytokines; tumor necrosis factor-α (TNF-α) upregulates LIF production and release via activation of the AP-1 transcription factor in fibroblasts and monocytes.^[26] Negative feedback loops maintain homeostasis in LIF signaling. LIF itself induces expression of suppressor of cytokine signaling 3 (SOCS3), which binds to the LIF receptor complex and inhibits further JAK-STAT activation, thereby suppressing additional LIF-mediated transcription including its own gene.^[27] In hypoxic tumor microenvironments, hypoxia-inducible factor-2α (HIF-2α) upregulates LIF transcription by binding to hypoxia response elements in the promoter, promoting tumor progression.^[28] Pathological dysregulation often leads to aberrant LIF overexpression. In rheumatoid arthritis, LIF mRNA and protein are hyper-expressed in synovial fibroblasts and macrophages due to IL-6 trans-signaling, which amplifies gp130-dependent pathways and sustains chronic inflammation in the synovium. Recent studies (as of 2024) have shown LIF promotes alternative activation in macrophages and amplifies profibrotic signaling in lung fibroblasts via autocrine loops.^[29]^[30]^[31]^[32]

Physiological roles

Maintenance of pluripotency in stem cells

Leukemia inhibitory factor (LIF) plays a critical role in maintaining the pluripotency and self-renewal of mouse embryonic stem (ES) cells by preventing their differentiation into lineages such as neuroectoderm. In the 1980s, seminal studies demonstrated that LIF enables the long-term culture of mouse ES cells in an undifferentiated state, without the need for feeder layers that previously supported their maintenance. This discovery highlighted LIF's ability to sustain the developmental potential of these cells, allowing indefinite propagation while preserving their capacity to contribute to all somatic lineages upon reintroduction into blastocysts.^[33] The mechanism underlying this effect involves the LIF-activated STAT3 signaling pathway, which integrates with the core pluripotency transcriptional network comprising Oct4, Sox2, and Nanog to suppress differentiation genes. Specifically, STAT3 activation by LIF promotes the expression of these factors, thereby reinforcing a self-renewing state and inhibiting the onset of neuroectoderm-specific gene programs that would otherwise drive lineage commitment.^[34] This pathway's necessity was confirmed through genetic studies showing that STAT3 is essential for ES cell pluripotency independent of other signaling influences.^[34] In contrast, human embryonic stem (ES) cells and induced pluripotent stem (iPS) cells exhibit reduced dependence on LIF alone for pluripotency maintenance, owing to differences in signaling pathway utilization between species. Human pluripotent stem cells primarily rely on fibroblast growth factor 2 (FGF2) combined with Activin/Nodal signaling to sustain their undifferentiated state, as LIF/STAT3 activation is insufficient by itself to prevent differentiation in these cells.^[35] This divergence reflects evolutionary adaptations in the regulatory networks governing human versus mouse pluripotency. In vivo, LIF contributes to the quiescence and maintenance of hematopoietic stem cells (HSCs) within the bone marrow niche. Studies in LIF knockout mice reveal a significant reduction in HSC numbers in the bone marrow and spleen, underscoring LIF's essential role in supporting the stem cell pool under physiological conditions. Administration of exogenous LIF in these models restores HSC populations, indicating a direct supportive function in the niche environment.^[36]

Functions in reproduction and development

Leukemia inhibitory factor (LIF) is essential for blastocyst implantation, where it is secreted by the uterine glandular epithelium and acts on the trophectoderm to activate STAT3 signaling, facilitating embryo attachment to the endometrium. In mice, targeted disruption of the LIF gene results in complete failure of blastocyst implantation, rendering homozygous females infertile despite normal ovarian function and blastocyst development; implantation can be rescued by exogenous LIF administration on gestational day 3.^[37] In humans, reduced endometrial LIF expression correlates with implantation failure, and rare heterozygous mutations in the LIF gene have been identified in women with unexplained infertility, including cases potentially affecting protein function and associated with recurrent in vitro fertilization failures.^[38] More recent studies have associated polymorphisms, such as the Val64Met variant (rs41281637), with lower circulating LIF levels and reduced success in IVF-ET.^[39] LIF contributes to placental development by promoting trophoblast differentiation, proliferation, and invasion into the maternal decidua, which is critical for establishing the feto-maternal interface. Inhibition of endogenous LIF during mid-gestation in mice disrupts trophoblast invasion, reduces placental vascularization, and impairs overall placentation, leading to intrauterine growth restriction.^[40] Knockout of the LIF receptor (LIFR) in mice causes severe placental defects, including disorganized trophoblast layers and impaired nutrient exchange, resulting in perinatal lethality within 24 hours of birth.^[41] In neural development, LIF directs the differentiation of neural precursor cells into astrocytes by activating JAK/STAT3 and MAPK pathways, thereby regulating gliogenesis in the developing central nervous system.^[42] LIF also exerts neuroprotective effects by enhancing neuronal survival and reducing apoptosis in models of central nervous system injury, such as following cortical lesions where LIF expression in reactive astrocytes supports repair processes.^[43] LIF regulates primordial germ cell (PGC) dynamics during embryonic migration by sustaining their survival and proliferation as they traverse the hindgut endoderm toward the genital ridges.^[44] Recent investigations have elucidated spatiotemporal LIF gradients in the uterine milieu, which dynamically guide embryo positioning and initial attachment during implantation in mice.^[45]

Pathological roles

Involvement in cancer

Leukemia inhibitory factor (LIF) is frequently overexpressed in various solid tumors, including breast, lung adenocarcinoma (LUAD), and colorectal cancers, where elevated levels correlate with adverse clinical outcomes. In breast cancer, LIF overexpression promotes tumorigenesis and metastasis, and is significantly associated with poorer relapse-free survival in patient cohorts. Similarly, in colorectal cancer, LIF is overexpressed in a substantial proportion of cases and serves as a negative regulator of p53, linking high expression to reduced patient survival. In non-small cell lung cancer (NSCLC), including LUAD subtypes, LIF is upregulated in tumor tissues compared to adjacent normal lung, with expression levels inversely correlated to overall prognosis, indicating its potential as a biomarker for disease severity.^[46]^[47]^[48] LIF exerts pro-tumorigenic effects through multiple mechanisms that drive cancer progression, particularly epithelial-mesenchymal transition (EMT) and metastasis. LIF promotes EMT in tumor cells via activation of the STAT3 pathway, leading to upregulation of miR-21 and acquisition of mesenchymal features that enhance invasiveness. This process is further amplified by LIF-mediated inhibition of the Hippo pathway, which reduces YAP phosphorylation, promotes its nuclear translocation, and fosters cell proliferation and metastatic potential. In inflammatory breast cancer (IBC), recent studies highlight LIF's role in conferring ferroptosis resistance; LIF/LIFR signaling sustains tumor growth by suppressing lipid peroxidation-dependent cell death, as demonstrated in preclinical models where pathway inhibition sensitizes cells to ferroptosis. Additionally, LIF enhances metastasis by modulating the LIFR/Hippo axis, where dysregulated signaling disrupts tumor-suppressive cascades and facilitates distant spread.^[49]^[50]^[51] In the tumor microenvironment (TME), LIF contributes to an immunosuppressive and pro-angiogenic niche, often through interactions with tumor-associated macrophages (TAMs). LIF expression is strongly associated with TAM infiltration across multiple tumor types, where it reprograms macrophages toward an M2-like phenotype that suppresses cytotoxic T-cell recruitment via downregulation of chemokines like CXCL9, thereby fostering immune evasion. TAM-derived or tumor-induced LIF further promotes angiogenesis by enhancing vascular endothelial growth factor secretion and matrix remodeling, supporting tumor vascularization and progression. A 2025 study revealed that cholangiocyte-derived LIF drives a pro-inflammatory and pro-fibrotic environment in primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC), correlating with increased fibrosis and immune activation.^[52]^[53]^[54] Therapeutic strategies targeting LIF signaling have shown promise in preclinical models for mitigating these pro-tumor effects. Small-molecule inhibitors of the LIF receptor (LIFR), such as EC359, effectively block downstream pathways, reducing tumor cell proliferation, invasiveness, and stemness while promoting apoptosis in models of triple-negative breast cancer and endometrial cancer. In vivo studies using patient-derived xenografts (PDXs) demonstrate that EC359 administration significantly attenuates tumor growth without notable toxicity, highlighting its potential to disrupt LIF-driven oncogenesis. These findings underscore LIF inhibition as a viable approach to counteract cancer progression in LIF-overexpressing malignancies.^[55]^[56]

Role in inflammation and autoimmunity

Leukemia inhibitory factor (LIF) functions as an acute-phase protein during inflammatory responses, with its expression rapidly upregulated in response to proinflammatory cytokines such as interleukin-6 (IL-6) and IL-1.^[12]^[57] This induction occurs in various tissues, including the liver and immune cells, contributing to the systemic acute-phase response by enhancing the production of other acute-phase proteins and modulating cytokine release.^[58] In macrophages, LIF promotes alternative activation toward an M2 phenotype, which is associated with resolution of inflammation and tissue repair, while also driving transcriptional programs that increase lipid accumulation within these cells.^[59] Recent 2024 studies highlight this role, demonstrating that LIF enhances M2 polarization markers such as Arg1 and Cd206, potentially limiting excessive proinflammatory responses in acute settings.^[31] In autoimmune diseases, LIF exhibits elevated levels in affected tissues, contributing to pathological processes. In rheumatoid arthritis (RA), LIF is overexpressed in the synovium, where it fosters a proinflammatory environment that promotes synovial hyperplasia and joint destruction through activation of the STAT3 signaling pathway.^[60]^[61] This STAT3-mediated effect sustains fibroblast-like synoviocyte proliferation and cytokine production, exacerbating cartilage and bone erosion.^[62] These findings underscore LIF's contribution to tissue-specific autoimmunity, distinct from its protective roles elsewhere. LIF displays a context-dependent duality in neuroinflammation, offering neuroprotection in acute white matter injury while promoting pathology in chronic conditions. Delayed administration of LIF, such as via intranasal delivery, has shown promise in 2025 preclinical models of traumatic brain injury, where it attenuates macrophage and microglial activation in white matter, reduces neurodegeneration, and preserves neurological outcomes even when initiated days post-injury.^[63] Conversely, in chronic inflammatory settings, LIF exerts pro-inflammatory effects, including stimulation of microglial proliferation and cytokine secretion that perpetuate ongoing tissue damage.^[64] This bidirectional nature is evident in its immunomodulatory actions, where LIF inhibits Th17 cell differentiation by suppressing key transcription factors like RORγt, thereby dampening pathogenic T-cell responses in autoimmunity.^[65] However, LIF also enhances B-cell survival and antibody production in certain autoimmune contexts, potentially amplifying humoral responses and contributing to disease persistence.^[66]

Therapeutic applications

Applications in stem cell culture

Leukemia inhibitory factor (LIF) is a critical component in the ex vivo culture of mouse embryonic stem (ES) cells and induced pluripotent stem (iPS) cells, where it promotes self-renewal and inhibits differentiation by activating the STAT3 signaling pathway.^[67] In standard protocols, recombinant mouse LIF is supplemented at a concentration of 1000 units per milliliter (U/mL) in serum-containing media, often on mitomycin C-treated mouse embryonic fibroblasts as feeders.^[67] For achieving ground-state pluripotency, LIF is combined with two small-molecule inhibitors of GSK3β (CHIR99021) and MEK (PD0325901), known as the LIF/2i condition, which supports dome-shaped colonies with enhanced homogeneity and epigenetic features resembling the pre-implantation epiblast.00348-4) This regimen, established in seminal work, enables long-term propagation without genetic manipulation and is widely adopted for deriving and maintaining naive mouse pluripotent stem cells.00348-4) In human ES cell (hESC) and iPS cell culture, LIF supplementation supports maintenance in certain defined, xeno-free media formulations, particularly when combined with inhibitors such as the Rho-associated kinase inhibitor (ROCKi, e.g., Y-27632) to enhance survival during passaging and single-cell dissociation. Typical concentrations range from 10 to 100 ng/mL in basal media like DMEM/F12 supplemented with bFGF and other factors, facilitating feeder-free expansion on matrices such as vitronectin or laminin-521.^[68] These protocols enable scalable, animal-component-free production suitable for research and potential clinical translation, though LIF alone does not suffice for long-term pluripotency maintenance in conventional primed-state hESCs, where FGF2 signaling predominates.^[69] Commercial recombinant LIF, primarily produced in Escherichia coli for cost-effective, non-glycosylated forms or in Chinese hamster ovary (CHO) cells for glycosylated variants with higher bioactivity, is available from suppliers like Sigma-Aldrich and STEMCELL Technologies.^[70] The global LIF market, valued at USD 1.34 billion in 2025, is projected to reach USD 2.90 billion by 2034, growing at a compound annual growth rate of 8.9%, largely driven by demand in stem cell therapy manufacturing and regenerative medicine applications.^[71] Despite its utility, LIF has limitations in human stem cell culture, as it fails to independently sustain self-renewal in primed hESCs due to inefficient STAT3 activation compared to mouse cells, often requiring complementary signals like Wnt or MEK/GSK3 inhibitors for naive-state conversion.^[69] Emerging alternatives include small-molecule STAT3 agonists, such as Colivelin or synthetic compounds that mimic LIF's effects on JAK/STAT signaling, offering potential for more stable, cytokine-free maintenance in defined media.30161-8)

Potential as therapeutic target

Leukemia inhibitory factor (LIF) has emerged as a promising therapeutic target due to its pleiotropic roles in inflammation, cancer, and neurodegeneration, with strategies focusing on both inhibition and agonism to modulate disease progression. Inhibitors targeting LIF or its receptor (LIFR) have shown potential in treating cancers and autoimmune conditions. For instance, anti-LIF antibodies, such as the antagonist 1G11 derived from human scFv phage display, have demonstrated anti-tumor efficacy in mouse models by blocking LIF signaling and reducing tumor growth. Similarly, LIFR antagonists have been implicated in suppressing pathological processes in breast cancer and rheumatoid arthritis (RA), where LIF promotes inflammation and tumor progression. In pancreatic cancer, neutralizing antibodies against LIF have blocked KRAS-driven tumorigenesis, highlighting LIF blockade as an attractive therapeutic approach. For example, a phase II trial is evaluating the anti-LIF antibody AZD0171 in combination with durvalumab and chemotherapy for metastatic pancreatic ductal adenocarcinoma (NCT04999969).^[72] These inhibitors are also under investigation for renal interstitial fibrosis, where LIF knockdown alleviated tissue injury in preclinical models. Agonistic approaches leverage recombinant LIF to promote neuroprotection and reproductive functions. Recombinant human LIF has been explored in early clinical studies for enhancing embryo implantation in infertility and preventing chemotherapy-induced peripheral neuropathy, but these trials did not demonstrate significant efficacy.^[73]^[74] In neuroprotection, intranasal delivery of recombinant LIF in preclinical spinal cord injury models attenuated gliosis, axonal damage, and microgliosis, preserving neurological function by activating anti-inflammatory pathways. For infertility, uterine administration of LIF has shown promise in enhancing embryo implantation in dysregulated cases, as LIF expression is critical for endometrial preparation during the implantation window. Despite these advances, challenges in targeting LIF stem from its pleiotropic effects, necessitating tissue-specific delivery to avoid off-target impacts on stem cell maintenance or immune regulation. Gene therapy approaches, such as CNS-targeted LIF expression vectors, have improved outcomes in experimental autoimmune encephalomyelitis models of multiple sclerosis (MS) by preserving myelin and limiting demyelination, offering a strategy to modulate LIF in autoimmunity. The global LIF market is projected to reach approximately USD 2.90 billion by 2034, driven by expanding applications in oncology and regenerative medicine.

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We undertook this study to investigate the prevalence of LIF gene alterations in women with unexplained infertility and with recurrent failure of implantation.
[36]
Leukemia Inhibitory Factor (LIF) Inhibition during Mid-Gestation ...
Our data suggest that LIF plays an important role in trophoblast invasion in vivo and may facilitate trophoblast-decidual-immune cell cross talk.
[37]
Leukemia Inhibitory Factor (LIF) Inhibition during Mid-Gestation ...
Oct 19, 2015 · Conversely, LIFR-knockout mice are perinatal lethal and die within 24 hours of birth [18]. In these mice, placental morphology is ...
[38]
Neural precursor differentiation into astrocytes requires signaling ...
The differentiation of precursor cells into neurons or astrocytes in the developing brain has been thought to be regulated in part by growth factors.
[39]
The role of the leukemia inhibitory factor receptor in neuroprotective ...
In addition to its regulation of neuronal signaling, one of the most prominent roles played by LIFR involves the development and maturation of neurons and glia.
[40]
Role of leukemia inhibitory factor and its receptor in mouse ...
Nov 1, 1994 · The pleiotropic cytokine leukemia inhibitory factor (LIF) is able to promote the growth of mouse primordial germ cells (PGCs) in culture.
[41]
Spatiotemporal functions of leukemia inhibitory factor in embryo ...
Nov 25, 2024 · We aimed to elucidate previously unexplored mechanisms by which Lif orchestrates successful embryo implantation by facilitating embryo-chamber formation.
[42]
LIF promotes tumorigenesis and metastasis of breast cancer through ...
Feb 15, 2014 · Furthermore, overexpression of LIF is significantly associated with a poorer relapse free survival in breast cancer patients. Taken together ...
[43]
LIF negatively regulates tumour-suppressor p53 through Stat3/ID1 ...
Oct 17, 2014 · LIF is overexpressed in a large percentage of human CRCs and is associated with a poor prognosis of CRC patients. Overexpression of LIF promotes ...
[44]
Leukemia inhibitory factor is involved in the pathogenesis of NSCLC ...
Jul 14, 2021 · The present results demonstrate that LIF is overexpressed in NSCLC, and that LIF can promote NSCLC development through activation of the STAT3 signaling ...Leukemia Inhibitory Factor... · Materials And Methods · ResultsMissing: seminal paper
[45]
Leukemia inhibitory factor promotes EMT through STAT3-dependent ...
This study reports that LIF promotes EMT in human tumor cells. Overexpression of LIF promotes tumor cells to acquire mesenchymal features.
[46]
Targeting LIF/LIFR signaling in cancer - ScienceDirect.com
This article reviews the significance of LIF/LIFR pathways and inhibitors that disrupt this process for the treatment of cancer.
[47]
Targeting the Leukemia Inhibitory Factor/Leukemia Inhibitory ... - NIH
Feb 25, 2025 · Targeting the Leukemia Inhibitory Factor/Leukemia Inhibitory Factor Receptor Axis reduces the growth of inflammatory breast cancer by promoting ferroptosis.
[48]
Therapeutic Targeting of LIF Overcomes Macrophage-mediated ...
LIF is associated with a macrophage-mediated immunosuppressive microenvironment in human cancer. A, Distribution of global LIF expression quartiles across 22 ...Abstract · Introduction · Results · Discussion
[49]
LIF regulates CXCL9 in tumor-associated macrophages ... - Nature
Jun 11, 2019 · Specifically, LIF generates a local immunosuppressive microenvironment in order to protect the embryo from the mother's immune system.
[50]
Tumor-derived LIF promotes chemoresistance via activating tumor ...
Sep 1, 2021 · We present that tumor-derived Leukemia inhibitory factor (LIF) induced by chemo drugs represses the chemo sensitivity of gastric tumor cells in a TAM-dependent ...
[51]
Leukemia inhibitory factor promotes human cholangiopathies, and ...
Aug 26, 2025 · Cholangiocyte-derived LIF promotes the formation of a pro-inflammatory and pro-fibrotic niche centred on damaged cholangiocytes. LIFR antagonism ...
[52]
EC359-A first-in-class small molecule inhibitor for targeting ...
EC359 reduced TNBC xenograft tumor growth in vivo ... Collectively, these results suggest that EC359 has potent anti-tumor activity on TNBC in preclinical models.
[53]
The LIFR Inhibitor EC359 Effectively Targets Type II Endometrial ...
Dec 13, 2023 · EC359 Reduced Patient-Derived Xenograft (PDX) Tumor Growth In Vivo. To test the efficacy of EC359 on in vivo tumor progression of Type II ECa ...
[54]
Cytokine-induced expression of leukemia inhibitory factor in renal ...
Recent observations indicate a role for LIF in inflammatory processes. To examine the potential involvement of LIF in the regulation of mesangial cell behavior, ...
[55]
Leukemia Inhibitory Factor Is an Anti-Inflammatory and Analgesic ...
Exogenously added LIF induces acute phase protein expression (Ryffel, 1993; Mehlen et al., 1997) and stimulates the production of proinflammatory cytokines ...
[56]
https://www.mdpi.com/1422-0067/24/24/17426
[57]
Leukemia inhibitory factor drives transcriptional programs that ...
Leukemia inhibitory factor (LIF) promotes a transcriptional signature that enhances macrophage alternative activation and lipid accumulation.Leukemia Inhibitory Factor... · 3. Results · 3.1 Lif Induces Distinct...
[58]
The levels of leukemia inhibitory factor in synovial tissues of patients ...
LIF appeared to be a cytokine produced by RA synovium leading to a proinflammatory secretion profile. Moreover, IL-4 and IL-1 ra may represent attenuated ...Missing: elevated STAT3
[59]
The role of leukemia inhibitory factor in autoimmune disorders
Apr 1, 2025 · The literature indicates that LIF has a dual role in autoimmune diseases. In RA, LIF plays an important role in the progression of joint damage ...Missing: destruction | Show results with:destruction
[60]
Increased levels of leukemia inhibitory factor in synovial fluid from ...
Conclusion: LIF is implicated as a potential mediator of the local or systemic inflammatory response or the joint destruction seen in inflammatory arthritis.Missing: STAT3 | Show results with:STAT3
[61]
Leukemia Inhibitory Factor as a late-stage treatment for delayed ...
Apr 7, 2025 · These results support the therapeutic potential of IN-LIF to reduce delayed neurodegeneration and improve neurological outcomes after mTBIs.
[62]
Leukemia inhibitory factor modulates production of inflammatory ...
These findings indicate LIF may have proinflammatory effects, although the direct influence of LIF on macrophages has not been investigated in detail.
[63]
Leukemia Inhibitory Factor Inhibits T Helper 17 Cell Differentiation ...
Aug 26, 2011 · This study reveals a critical role for LIF in regulating Th17 cell differentiation and provides insights into the mechanisms of action of NPC therapy in MS.
[64]
Leukemia inhibitory factor tips the immune balance towards ...
We reveal that in MS patients the LIF receptor (LIFR) was strongly increased on circulating T cells.
[65]
https://www.sciencedirect.com/science/article/pii/S1074761311003025
[66]
Human Recombinant LIF | STEMCELL Technologies
$$88.00LIF plays a role in implantation by regulating proliferation, invasion, and differentiation of trophoblast following the blastocyst attachment.
[67]
LIF/STAT3 signaling fails to maintain self-renewal of ... - PubMed - NIH
Nevertheless, despite the functional activation of the LIF-STAT3 signaling pathway, human LIF is unable to maintain the pluripotent state of hESCs. Feeder-free ...
[68]
https://www.stemcell.com/products/human-recombinant-lif.html
[69]
Leukemia Inhibitory Factor (LIF) Market Size to Hit USD 2.90 Bn by ...
Apr 1, 2025 · The global leukemia inhibitory factor (lif) market size is calculated at USD 1.34 billion in 2025 and is forecasted to reach around USD 2.90 billion by 2034.