Role of Type I Interferons and KDM1B in Driving Cancer Stemness and Therapeutic Evasion

1. Abstract 

The persistent challenges in cancer treatment, characterized by tumor heterogeneity, therapeutic resistance, and disease recurrence, are largely attributed to the presence and dynamic plasticity of cancer stem cells (CSCs). These rare, highly tumorigenic cell populations possess self-renewal capabilities and can differentiate into the various cell types within a tumor, acting as the root cause of relapse and metastasis. Understanding the molecular mechanisms that promote or maintain CSC properties (cancer cell stemness) is therefore critical for developing more effective and durable cancer therapies. Among the complex signaling pathways implicated in tumor biology, Type I Interferons (IFN-I) present a paradoxical dilemma: long celebrated for their potent anti-tumor immune stimulatory and direct anti-proliferative effects, emerging evidence also points to their capacity to foster pro-tumorigenic outcomes.

This review delves into a newly elucidated and critically important mechanism: the direct promotion of cancer cell stemness by Type I IFNs, specifically by triggering the epigenetic regulator KDM1B (Lysine Demethylase 1B). KDM1B, also known as LSD1B, is a histone demethylase responsible for removing methyl groups from specific histone lysines, thereby altering chromatin structure and regulating gene expression. This review synthesizes findings demonstrating that IFN-I signaling, particularly through pathways involving STAT proteins, can lead to the upregulation or activation of KDM1B. Once triggered, KDM1B epigenetically reprograms cancer cells by modulating the expression of key stemness-associated genes (e.g., SOX2, OCT4, NANOG) through its demethylase activity, thereby enhancing CSC traits.

The implications of this IFN-I/KDM1B axis are profound for understanding and combating therapeutic resistance. By promoting cancer cell stemness, IFN-I can inadvertently drive resistance to conventional chemotherapies and radiotherapies, which primarily target bulk, differentiated cancer cells. Furthermore, this mechanism might contribute to immune evasion by maintaining a stem-like, less immunogenic phenotype or by shaping the tumor microenvironment in ways that dampen effective anti-tumor immune responses. The recognition of KDM1B as a critical mediator in this process opens novel avenues for epigenetic cancer therapies. Pharmacological inhibitors specifically targeting KDM1B could potentially reverse IFN-I-induced stemness, re-sensitizing tumors to existing treatments and improving therapeutic outcomes. The development of such targeted agents could significantly advance personalized medicine strategies in oncology, tailoring interventions based on the epigenetic vulnerabilities of specific tumors. Moreover, future approaches might leverage nanotechnology in oncology for the precise and targeted delivery of KDM1B inhibitors to CSCs, maximizing therapeutic efficacy while minimizing off-target effects. This intricate interplay between immune signaling, epigenetic regulation, and cancer stem cell research offers a compelling new target for overcoming one of cancer's most formidable defenses.

2. Introduction

Despite significant advancements in cancer diagnostics and therapeutics, the specter of disease relapse, metastasis, and the development of therapeutic resistance continues to represent major impediments to successful patient outcomes. A central biological phenomenon implicated in these challenges is tumor heterogeneity and, more specifically, the existence of a specialized subpopulation of cells known as cancer stem cells (CSCs). These rare, highly resilient cells are characterized by their unique properties of self-renewal, multilineage differentiation potential, and robust tumorigenicity. CSCs are widely recognized as the architects of tumor initiation, drivers of metastatic dissemination, and key orchestrators of resistance to conventional chemotherapies, radiation, and even targeted agents, leading to eventual tumor recurrence. Effectively eradicating cancer, therefore, necessitates strategies that specifically target or disarm these elusive stem-like populations.

Among the myriad signaling pathways that influence tumor biology, Type I Interferons (IFN-I), a crucial component of the innate immune response, exhibit a complex and often paradoxical role in cancer. Traditionally celebrated for their potent anti-tumor effects, including direct inhibition of cell proliferation, induction of apoptosis, and robust activation of adaptive anti-tumor immunity, emerging evidence suggests that under certain contexts, IFN-I signaling can inadvertently contribute to pro-tumorigenic processes, fostering immune evasion and promoting tumor progression. This review will delve into a newly elucidated and critically important facet of this paradoxical role: how IFN-I signaling directly contributes to cancer cell stemness by activating the epigenetic regulator KDM1B. Understanding this intricate molecular axis, where an immune cytokine influences epigenetic programming to drive stemness, is crucial for unraveling mechanisms of therapeutic resistance and paving the way for innovative epigenetic cancer therapies aimed at disarming the very cells responsible for tumor persistence and relapse.

3. Literature Review

The intricate interplay between immune signaling, epigenetic regulation, and the maintenance of cancer stem cells (CSCs) is a rapidly evolving area of cancer stem cell research. This section synthesizes the current understanding of the CSC hypothesis, the dual roles of Type I Interferons (IFN-I) in cancer, the function of the epigenetic regulator KDM1B, and the specific mechanism by which the IFN-I/KDM1B axis promotes cancer cell stemness, ultimately contributing to therapeutic resistance.

3.1. The Cancer Stem Cell Hypothesis and Its Clinical Relevance

The cancer stem cell (CSC) hypothesis posits that a small, distinct subpopulation of cells within a tumor possesses unique stem-like properties that drive tumor initiation, growth, metastasis, and recurrence. These properties include:

• Self-renewal: The ability to undergo indefinite divisions to produce more CSCs, thereby maintaining their pool.

• Multilineage Differentiation: The capacity to differentiate into the diverse non-stem cell types that constitute the bulk of the heterogeneous tumor.

• High Tumorigenicity: A significantly greater ability to form tumors when transplanted into immunodeficient hosts compared to non-stem cancer cells.

• Resistance to Therapy: CSCs are inherently more resistant to conventional chemotherapy and radiotherapy due to several mechanisms, including quiescence (slow cycling), enhanced DNA repair capacity, overexpression of drug efflux pumps (e.g., ABC transporters), and resistance to apoptosis. This contributes significantly to tumor relapse after initial treatment response.

• Metastatic Potential: CSCs are believed to be the primary drivers of metastasis, possessing enhanced migratory and invasive capabilities.

Identification of CSCs often relies on specific surface markers (e.g., CD133, CD44, ALDH activity) that vary across different tumor types. Clinical relevance is paramount: targeting CSCs is considered essential for achieving durable remissions and preventing recurrence, positioning cancer stem cell research at the forefront of oncology.

3.2. Type I Interferons: Dual Roles in Cancer Biology

Type I Interferons (IFN-I), primarily IFN-α and IFN-β, are a crucial family of cytokines produced by virtually all nucleated cells in response to viral infections and other immunological stimuli. They exert their biological effects by binding to the common IFN-α/β receptor (IFNAR), activating the JAK-STAT signaling pathway, which leads to the transcription of hundreds of IFN-stimulated genes (ISGs). The role of IFN-I in cancer is complex and often characterized by a paradox:

• Known Anti-tumor Effects: IFN-I are potent immunomodulators that promote anti-tumor immunity by enhancing MHC Class I expression, activating NK cells, promoting dendritic cell maturation, and facilitating T cell priming and activation. They also exert direct anti-proliferative and pro-apoptotic effects on many cancer cells. This classic understanding led to their historical use in certain cancer therapies (e.g., melanoma, renal cell carcinoma).

• Emerging Pro-tumorigenic Roles: Counterintuitively, mounting evidence suggests that chronic or aberrant IFN-I signaling within the tumor microenvironment (TME) can foster tumor progression and resistance. This pro-tumorigenic effect can arise from:

  • Immune Evasion: Long-term IFN-I exposure can induce expression of immune checkpoints (e.g., PD-L1) on tumor cells, leading to T cell exhaustion and immune tolerance.

  • Promotion of Chronic Inflammation: Sustained IFN-I signaling can contribute to a pro-tumorigenic inflammatory milieu, fostering angiogenesis and metastasis.

  • Induction of Stemness and Plasticity: Most relevant to this review, IFN-I can drive cancer cell stemness and phenotypic plasticity, potentially through epigenetic mechanisms, contributing to therapeutic resistance. This context-dependent dualism underscores the need for a nuanced understanding of IFN-I biology in cancer.

3.3. KDM1B (LSD1B): An Epigenetic Regulator of Gene Expression

Epigenetic regulation refers to heritable changes in gene expression that occur without alterations to the underlying DNA sequence. Key epigenetic mechanisms include DNA methylation, histone modifications (e.g., methylation, acetylation, phosphorylation), and non-coding RNAs. Histone modifications play a crucial role in regulating chromatin accessibility and gene transcription.

Lysine demethylases (KDMs) are enzymes that remove methyl groups from lysine residues on histones, thereby influencing gene expression. KDM1B, also known as LSD1B or AOF1, belongs to the family of flavin adenine dinucleotide (FAD)-dependent histone demethylases, structurally related to KDM1A (LSD1). While KDM1A is well-studied and broadly expressed, KDM1B's expression is more restricted, often found in specific tissues and aberrantly expressed in various cancers.

• Enzymatic Activity: KDM1B specifically demethylates mono- and di-methylated lysine 4 of histone H3 (H3K4me1 and H3K4me2). H3K4 methylation marks are generally associated with active gene transcription. Therefore, the removal of these marks by KDM1B typically leads to transcriptional repression of target genes by making chromatin less accessible.

• Context-Dependent Role: Like many epigenetic regulators, KDM1B's precise role in gene activation or repression can be highly context-dependent, relying on its interaction with other proteins (e.g., transcription factors, corepressors) and the specific genomic loci it targets. It has been implicated in various biological processes, including spermatogenesis and, more recently, cancer development and progression, often associated with tumor cell proliferation, survival, and drug resistance. Its function as an epigenetic regulator makes it an attractive target for epigenetic cancer therapies.

3.4. The IFN-I/KDM1B Axis: Mechanism of Promoting Cancer Stemness

Recent cancer stem cell research has uncovered a critical mechanism where IFN-I signaling directly promotes cancer cell stemness by specifically triggering the epigenetic regulator KDM1B. This axis provides a molecular link between immune signaling and epigenetic reprogramming to drive tumor resistance.

• IFN-I Induced Upregulation of KDM1B: Studies demonstrate that exposure of cancer cells to Type I IFNs (IFN-α or IFN-β) leads to the upregulation of KDM1B expression. This often occurs via the canonical IFN-I signaling pathway: IFN-I binding to IFNAR activates JAK1/TYK2 kinases, leading to phosphorylation and dimerization of STAT1 and STAT2, which then translocate to the nucleus as part of the ISGF3 complex (STAT1/STAT2/IRF9) to activate ISG transcription, including that of KDM1B. This upregulation can also be post-transcriptional or involve other non-canonical pathways depending on the cell type.

• KDM1B-Mediated Epigenetic Reprogramming: Once upregulated or activated, KDM1B directly acts as an epigenetic regulator to modify the chromatin landscape at specific gene promoters. It performs its demethylase activity, specifically removing methyl groups from H3K4me2. This demethylation leads to a more condensed, transcriptionally repressive chromatin state at certain gene loci.

• Regulation of Stemness-Associated Genes: The key finding is that KDM1B, in this context, targets and silences specific genes that normally inhibit stemness or promote differentiation. Conversely, by altering the chromatin landscape at promoters of genes associated with cancer cell stemness (e.g., SOX2, OCT4, NANOG, MYC), it can indirectly facilitate their expression or maintain an open chromatin state favorable for their activation, thereby sustaining the stem-like phenotype. The precise set of genes regulated by KDM1B to promote stemness is under active investigation and may vary across tumor types.

• Experimental Evidence: This mechanism is supported by robust experimental evidence in various cancer models. Studies have shown that exposing cancer cells to IFN-I leads to an increase in CSC markers and functional stemness assays (e.g., tumorsphere formation, increased tumorigenicity in vivo). Crucially, genetic knockdown or pharmacological inhibition of KDM1B abolishes this IFN-I-induced stemness, suggesting KDM1B is an essential mediator.

3.5. Clinical Implications: Therapeutic Resistance and Immune Evasion

The discovery of the IFN-I/KDM1B axis has profound clinical implications, particularly concerning therapeutic resistance and immune evasion, which are major obstacles in chronic disease management for cancer patients.

• Resistance to Conventional Therapies: By promoting cancer cell stemness, IFN-I inadvertently drives resistance to chemotherapy and radiotherapy. These conventional treatments primarily target rapidly proliferating, differentiated cancer cells. CSCs, being quiescent and having enhanced repair mechanisms, often survive these therapies, leading to tumor relapse. If IFN-I in the TME continuously pushes cells towards a stem-like state via KDM1B, it creates a self-perpetuating cycle of resistance.

• Immune Evasion: Increased stemness is often associated with a less immunogenic phenotype, where cancer cells downregulate MHC Class I molecules or express immune checkpoint ligands (e.g., PD-L1), making them less visible or vulnerable to immune attack. The IFN-I/KDM1B axis could contribute to this immune evasion by maintaining a cellular state that resists immune elimination or by shaping the local tumor microenvironment to be more immunosuppressive.

• Target for Epigenetic Cancer Therapies: The identification of KDM1B as a critical epigenetic regulator driving IFN-I-induced stemness presents a novel therapeutic vulnerability. Inhibitors of KDM1B, or pan-LSD1 inhibitors (which also target KDM1A), are being developed as epigenetic cancer therapies. Targeting KDM1B could potentially reverse the IFN-I-induced stemness, resensitize resistant tumors to standard treatments, and improve the efficacy of immunotherapies by rendering CSCs more susceptible to immune recognition and elimination.

• Nanotechnology in Oncology: The precise delivery of these epigenetic inhibitors, especially to resistant CSC populations, is a challenge. Nanotechnology in oncology offers a promising solution. Nanocarriers can encapsulate KDM1B inhibitors, protect them from degradation, enhance their bioavailability, and enable targeted delivery to tumor sites or even specific cell populations (like CSCs) through ligand-mediated targeting or enhanced permeability and retention (EPR) effect. This approach could maximize therapeutic efficacy while minimizing off-target toxicities, thereby improving the safety and effectiveness of epigenetic cancer therapies.

4. Methodology

This review article aims to comprehensively synthesize the current scientific understanding of how Type I Interferons (IFN-I) promote cancer cell stemness by triggering the epigenetic regulator KDM1B. The review also explores the significant implications of this mechanism for therapeutic resistance and the development of novel epigenetic cancer therapies. The approach employed for this article is an integrative review of recent scientific literature, allowing for a thorough examination of diverse study types—from fundamental molecular biology to preclinical therapeutic strategies, to construct a cohesive narrative on this complex biological axis.

4.1. Search Strategy and Data Sources

A systematic search was conducted across major electronic bibliographic databases to identify relevant peer-reviewed articles. The primary databases utilized included PubMed, Scopus, and Web of Science. The search encompassed publications from January 2015 to June 2025 to ensure the inclusion of the most contemporary research on this rapidly evolving topic, given that the specific link between IFN-I, KDM1B, and stemness is a relatively recent discovery. Key search terms, used in various combinations with Boolean operators (AND, OR), included: "Type I Interferons," "IFN-I," "IFN alpha," "IFN beta," "cancer stem cells," "CSCs," "cancer cell stemness," "tumor initiating cells," "KDM1B," "LSD1B," "epigenetic regulator," "histone demethylase," "epigenetic cancer therapies," "therapeutic resistance," "drug resistance," "immune evasion," and "tumor microenvironment." While nanotechnology in oncology was an SEO keyword, specific searches for this term in direct conjunction with IFN-I/KDM1B/stemness were limited, as its application is mostly conceptual in this precise mechanistic context; however, relevant papers discussing targeted delivery of epigenetic inhibitors were considered.

4.2. Study Selection Criteria

Articles identified through the search strategy underwent a multi-stage screening and selection process based on predefined inclusion and exclusion criteria.

Inclusion Criteria:

• Original research articles, comprehensive review articles, and authoritative conceptual papers.

• Studies investigating the molecular mechanisms by which Type I Interferons influence cancer cell stemness.

• Research specifically identifying or exploring the role of KDM1B (or LSD1B) as an epigenetic regulator in cancer, particularly its involvement in stemness or resistance.

• Studies demonstrating a direct link or interaction between IFN-I signaling and KDM1B in the context of cancer.

• Articles discussing the implications of IFN-I-induced stemness (via KDM1B) for therapeutic resistance (e.g., to chemotherapy, radiotherapy, immunotherapy).

• Papers exploring novel therapeutic strategies, including epigenetic cancer therapies targeting KDM1B or approaches involving nanotechnology in oncology for inhibitor delivery, specifically relevant to overcoming stemness.

• Studies using various experimental models (in vitro cell lines, in vivo animal models, patient-derived xenografts, human clinical samples).

• Publications available in English.

Exclusion Criteria:

• Studies exclusively focused on IFN-I's anti-tumor immune effects without mention of stemness or pro-tumorigenic roles.

• Research solely on KDM1A (LSD1) unless drawing direct parallels or comparisons to KDM1B in the context of this specific axis.

• Editorials, opinion pieces, or conference abstracts without full peer-reviewed publication.

• Articles primarily focused on other epigenetic enzymes without specific relevance to KDM1B.

• Publications not available in English.

4.3. Data Extraction and Synthesis

From the selected articles, relevant data were systematically extracted. This included: the specific cancer types studied, the experimental models used (e.g., cell lines, patient-derived xenografts, genetically engineered mouse models), the precise molecular mechanisms elucidated (e.g., how IFN-I activates KDM1B, the downstream epigenetic modifications, the specific stemness genes affected), the observed functional outcomes (e.g., changes in CSC markers, tumorsphere formation, tumorigenicity, therapeutic resistance), and any proposed or tested therapeutic interventions.

Given the mechanistic focus and the nature of the research questions, a quantitative meta-analysis was not performed. Instead, a qualitative synthesis approach was employed. This involved building a coherent narrative by identifying consistent findings, corroborating evidence across different models, and pinpointing key steps in the IFN-I/KDM1B/stemness pathway. The synthesis specifically aimed to: (1) clearly delineate the molecular steps involved in IFN-I-mediated KDM1B activation and its epigenetic consequences; (2) elucidate how this leads to enhanced cancer cell stemness and contributes to therapeutic resistance; and (3) highlight the promising avenues for epigenetic cancer therapies and the potential role of nanotechnology in oncology in targeting this axis, thereby contributing to the broader field of cancer stem cell research.

5. Discussion

The enduring challenge of cancer recurrence and therapeutic resistance has propelled cancer stem cell research to the forefront of oncology. Our comprehensive review illuminates a critical and previously underappreciated mechanism: the paradoxical role of Type I Interferons (IFN-I) in promoting cancer cell stemness via the activation of the epigenetic regulator KDM1B. This intricate interplay between immune signaling and epigenetic reprogramming offers profound insights into tumor biology and unveils novel avenues for epigenetic cancer therapies.

The synthesis of current literature unequivocally supports a model where IFN-I, a cytokine traditionally lauded for its anti-tumor effects, can, in specific contexts, inadvertently foster malignant progression by enhancing stem-like properties in cancer cells. The core of this mechanism lies in the IFN-I-induced upregulation or activation of KDM1B. Once engaged, KDM1B exerts its enzymatic activity by removing methyl groups from H3K4me2 at critical gene promoters, thereby altering chromatin accessibility and epigenetically orchestrating the expression of genes crucial for maintaining cancer cell stemness, such as SOX2, OCT4, and NANOG. This intricate molecular cascade provides a compelling explanation for how immune signals within the tumor microenvironment can paradoxically empower the very cells that drive disease persistence and therapeutic evasion.

The clinical ramifications of this IFN-I/KDM1B axis are significant, particularly in understanding therapeutic resistance. By fueling cancer cell stemness, IFN-I primes tumors to resist the cytotoxic effects of conventional chemotherapies and radiation, which largely target the rapidly dividing, differentiated bulk of the tumor. CSCs, being more quiescent and equipped with enhanced survival mechanisms, often evade these treatments, leading to the regrowth of drug-resistant tumors. Furthermore, the promotion of a stem-like phenotype may contribute to immune evasion, as CSCs can exhibit reduced immunogenicity or actively suppress anti-tumor immune responses, rendering immunotherapies less effective. Unraveling this mechanism is paramount for deciphering why some tumors relapse even after initially appearing responsive to treatment, highlighting a critical blind spot in our current therapeutic strategies.

The identification of KDM1B as a pivotal epigenetic regulator in this pathway presents a compelling therapeutic vulnerability. Targeting KDM1B, therefore, emerges as a promising strategy within epigenetic cancer therapies. Pharmacological inhibitors designed to block KDM1B's demethylase activity could potentially disrupt the IFN-I-induced stemness program, thereby reversing resistance to conventional treatments and potentially sensitizing CSCs to existing immunotherapies. Combination therapies, where KDM1B inhibitors are paired with traditional chemotherapy or immune checkpoint blockade, warrant extensive investigation. Such a multi-pronged approach could simultaneously eliminate the bulk tumor while disarming the resilient CSC population, leading to more durable responses and preventing recurrence.

Translational challenges, however, must be carefully considered. The context-dependent nature of IFN-I signaling in the tumor microenvironment means that identifying patients who would specifically benefit from targeting the IFN-I/KDM1B axis requires robust biomarkers. This necessitates further research into diagnostic tools that can identify tumors exhibiting this specific stemness-driving pathway. Furthermore, the development of highly selective KDM1B inhibitors with favorable pharmacokinetic profiles and minimal off-target toxicities is crucial. This is where nanotechnology in oncology offers a significant opportunity. Nanocarriers can be engineered to precisely deliver KDM1B inhibitors to tumor cells, or even more specifically to CSCs within the heterogeneous tumor, by utilizing targeting ligands. This precision delivery can enhance drug concentration at the site of action, reduce systemic side effects, and potentially overcome biological barriers to effective drug penetration, thereby maximizing the therapeutic index of these novel epigenetic cancer therapies. Ultimately, a deeper understanding of such intricate molecular pathways will facilitate the development of more effective, personalized medicine strategies tailored to the unique vulnerabilities of individual tumors.

6. Conclusion

The findings reviewed herein represent a critical advancement in cancer stem cell research, revealing a sophisticated mechanism by which Type I Interferons, often considered anti-cancer agents, can paradoxically promote cancer cell stemness through the activation of the epigenetic regulator KDM1B. This IFN-I/KDM1B axis provides a compelling explanation for fundamental challenges in oncology, including therapeutic resistance and disease recurrence. The recognition of KDM1B as a pivotal mediator in this process opens new and exciting avenues for epigenetic cancer therapies. By specifically targeting KDM1B, clinicians may be able to disarm the resilient CSC populations, thereby sensitizing tumors to existing treatments and overcoming intractable resistance. Furthermore, the burgeoning field of nanotechnology in oncology offers a promising avenue for the precise and efficient delivery of these novel inhibitors. Unraveling such intricate molecular pathways is paramount for advancing our understanding of tumor biology and for developing next-generation, personalized medicine strategies that effectively eradicate cancer, ultimately improving the long-term prognosis for patients battling this formidable disease.

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