Dual Roles of Interleukin-1β in Tumor Immune Regulation and Its Therapeutic Potential

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In the field of tumor immunology, the complex regulatory network of inflammation and immune response has always been a research hotspot. Interleukin-1 β (IL-1 β), as a key pro-inflammatory cytokine, plays a "double agent" role in the interaction between the immune system and the tumor microenvironment. On the one hand, IL-1 β activates anti-tumor immune mechanisms by inducing acute inflammatory responses, directly or indirectly killing cancer cells; On the other hand, under specific conditions, it may accelerate tumor progression by promoting angiogenesis, tumor cell proliferation, and other pathways. The duality of this function makes it a highly controversial and promising target in tumor immunotherapy research.

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Dual Roles of Interleukin-1β in Tumor Immune Regulation and Its Therapeutic Potential

Introduction

In the field of tumor immunology, the complex regulatory network between inflammation and immune response has always been a research hotspot. As a key pro-inflammatory cytokine, interleukin-1β (IL-1β) plays the role of a "double-agent" in the interaction between the immune system and the tumor microenvironment. On one hand, IL-1β activates anti-tumor immune mechanisms through inducing acute inflammatory responses, directly or indirectly killing cancer cells; on the other hand, under certain conditions, it may accelerate tumor progression by promoting angiogenesis, tumor cell proliferation and other pathways. This functional duality makes it a highly controversial yet promising target in tumor immunotherapy research. This article systematically elaborates on the molecular characteristics, signal transduction mechanisms, dual roles in the tumor microenvironment and application prospects in cell therapy of IL-1β, providing a theoretical basis for in-depth understanding of the relationship between inflammation and tumors and the development of novel immunotherapeutic strategies.

Ⅰ,Molecular Characteristics and Signal Transduction Mechanisms of IL-1β

IL-1β is an important member of the IL-1 family. As a typical pro-inflammatory cytokine, it plays a core role in the initiation and regulation of innate and adaptive immune responses. Different from most secreted proteins, IL-1β is initially synthesized as an inactive precursor form (Pro-IL-1β), and its maturation process depends on the activation of intracellular signaling complexes called inflammasomes. Inflammasomes are multi-protein complexes composed of intracellular pattern recognition receptors (PRRs), adapter protein ASC and effector protein caspase-1, which can sense pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). When cells are subjected to infection, tissue damage or other forms of cellular stress, inflammasomes are activated, and caspase-1 undergoes self-cleavage to become activated, which then cleaves Pro-IL-1β into mature IL-1β with biological activity.

Various cell types can produce and release IL-1β, among which macrophages, monocytes and dendritic cells are the main secretory cells. In addition, neutrophils, synoviocytes, endothelial cells and other cells can also synthesize IL-1β under specific stimuli. Upon receiving external stimulus signals, these cells initiate the expression and secretion process of IL-1β through complex regulatory mechanisms. After being released into the extracellular space, mature IL-1β exerts biological effects by binding to specific receptors on target cells. The receptor system of IL-1β consists of IL-1 receptor type I (IL-1RI), IL-1 receptor accessory protein (IL-1RAcP) and IL-1 receptor antagonist (IL-1Ra). IL-1β first binds to IL-1RI with high affinity, then recruits IL-1RAcP to form a functional receptor complex, while IL-1Ra inhibits IL-1β signal transduction by competitively binding to IL-1RI, forming an elaborate negative feedback regulatory mechanism.

After IL-1β binds to its receptor, signal transduction is carried out through a cascade reaction of a series of intracellular signaling molecules. Its main signal transduction pathways include nuclear factor-κB (NF-κB) pathway, mitogen-activated protein kinase (MAPK) pathway, etc. In the NF-κB pathway, the formation of the receptor complex activates downstream molecules such as myeloid differentiation factor 88 (MyD88), IL-1 receptor-associated kinases (IRAKs) and tumor necrosis factor receptor-associated factor 6 (TRAF6), which in turn activate the IκB kinase (IKK) complex. The IKK complex phosphorylates IκB protein, causing it to dissociate from NF-κB and be degraded. The released NF-κB transcription factor enters the nucleus and initiates the expression of various inflammatory mediators and immunoregulatory molecules. The activation of the MAPK pathway further regulates the expression of inflammation-related genes by phosphorylating molecules such as p38, c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK). The synergistic effect of these signaling pathways collectively mediates the inflammatory response and immune activation effects induced by IL-1β.

Ⅱ，Dual Roles of IL-1β in the Tumor Microenvironment

The tumor microenvironment is a complex ecosystem composed of tumor cells, immune cells, stromal cells and extracellular matrix, in which inflammation plays an important role. As a key inflammatory mediator, IL-1β exhibits significant functional duality in the tumor microenvironment, which can not only exert anti-cancer effects by activating anti-tumor immune responses, but also may promote tumor progression through biological processes related to tumor development.

In terms of anti-tumor immunity, IL-1β can induce acute inflammatory responses to kill cancer cells through multiple mechanisms. Acute inflammatory responses can recruit a large number of immune cells to infiltrate into tumor tissues, including neutrophils, macrophages, dendritic cells and T cells. IL-1β can directly activate dendritic cells, promote their maturation and antigen-presenting ability, enhance the activation and proliferation of T cells, thereby initiating specific anti-tumor immune responses. Studies have shown that IL-1β treatment can significantly increase the expression levels of co-stimulatory molecules (such as CD80, CD86) on the surface of dendritic cells and promote their secretion of pro-inflammatory cytokines such as IL-12, thereby enhancing the recognition and killing ability of cytotoxic T lymphocytes (CTL) against tumor cells. In addition, IL-1β can also activate natural killer (NK) cells and natural killer T (NKT) cells, enhance their cytotoxic activity, and directly exert anti-tumor effects.

However, under chronic inflammatory conditions, IL-1β may promote tumor progression through multiple pathways. IL-1β can induce the expression of factors such as vascular endothelial growth factor (VEGF) and matrix metalloproteinases (MMPs) in the tumor microenvironment, promote tumor angiogenesis and matrix remodeling, and provide nutritional support and channels for the growth and metastasis of tumor cells. At the same time, IL-1β can also directly act on tumor cells, promote the proliferation, survival, invasion and metastasis of tumor cells by activating signaling pathways such as NF-κB. In certain tumor types, IL-1β can also enhance the stem cell characteristics and drug resistance of tumor cells by inducing epithelial-mesenchymal transition (EMT), increasing the difficulty of tumor treatment. In addition, IL-1β may also promote tumor progression by inhibiting anti-tumor immune responses, such as inducing the differentiation and function of regulatory T cells (Treg), inhibiting the activity of effector T cells, thereby forming an immunosuppressive microenvironment.

The functional duality of IL-1β in the tumor microenvironment is regulated by multiple factors, including the local concentration of IL-1β, duration, tumor type, and the composition of other cytokines and immune cells in the microenvironment. In the acute inflammation stage, moderate release of IL-1β can effectively activate anti-tumor immunity; while in the chronic inflammation state, sustained high concentration of IL-1β may promote tumor progression. In-depth understanding of the mechanism of IL-1β under different tumor microenvironment conditions is crucial for the development of IL-1β-targeted tumor therapeutic strategies.

Ⅲ，Mechanism of IL-1β-induced Th9 Cell Differentiation and Its Anti-tumor Potential

The differentiation and functional regulation of helper T cells (Th cells) is a key link in adaptive immune responses, and different subtypes of Th cells play different roles in tumor immunity. In recent years, Th9 cells, as a newly discovered subtype of Th cells, have attracted widespread attention due to their strong anti-tumor activity. Th9 cells mainly exert biological functions by secreting IL-9 and have shown significant anti-tumor effects in various tumor models. Studies have found that IL-1β plays a unique and important role in the regulation of Th9 cell differentiation, providing new ideas for tumor immunotherapy.

The classical Th9 cell differentiation model believes that naive CD4⁺ T cells can differentiate into Th9 cells under the combined action of IL-4 and transforming growth factor-β (TGF-β). However, recent studies have revealed the key role of IL-1β in Th9 cell differentiation, and found that IL-1β can replace TGF-β to induce Th9 cell subsets with stronger anti-tumor activity. Under the combined stimulation of IL-4 and IL-1β, naive CD4⁺ T cells can more effectively differentiate into IL-9-producing Th9 cells. Compared with classical Th9 cells induced by IL-4+TGF-β, Th9 cells induced by IL-4+IL-1β show a unique gene expression profile, especially high expression of genes related to cytotoxic T effector cells, such as granzyme B and perforin, making them have stronger direct tumor-killing ability.

The molecular mechanism of IL-1β-induced Th9 cell differentiation involves the synergistic regulation of multiple signaling pathways and transcription factors. IL-1β binds to IL-1RI on the surface of Th cells, activates the downstream NF-κB signaling pathway. After entering the nucleus, members of the NF-κB family (such as p65) can directly bind to the promoter region of the IL-9 gene and promote the transcriptional expression of IL-9. At the same time, IL-1β can also enhance the activity of transcription factor PU.1 by activating the MAPK pathway. As a key transcription factor for Th9 cell differentiation, PU.1 can bind to the IL-9 gene promoter and promote its expression. In addition, IL-1β can also promote Th9 cell differentiation by inhibiting the expression of B-cell lymphoma 6 (BCL6). BCL6 is a known inhibitor of Th9 cell differentiation, and IL-1β down-regulates the expression of BCL6, relieving its inhibitory effect on IL-9 gene transcription, thereby promoting the differentiation of Th9 cells.

The regulatory role of IL-1β in Th9 cell differentiation is more prominent under IL-2 signal-limited conditions. IL-2 is an essential cytokine for Th9 cell differentiation, which promotes the differentiation and survival of Th9 cells by activating the STAT5 signaling pathway. However, in the tumor microenvironment, the level of IL-2 is often low, limiting the differentiation of Th9 cells. Studies have found that IL-1β can make Th9 cells more sensitive to low levels of IL-2, so that they can still effectively induce Th9 cell differentiation under IL-2-deficient conditions. This effect is mainly achieved by IL-1β inhibiting the activity of BCL6. BCL6 not only directly inhibits the expression of IL-9, but also inhibits the expression of IL-2 receptors. IL-1β increases the expression level of IL-2 receptors by down-regulating BCL6, enhances the sensitivity of Th cells to IL-2, and thereby promotes the differentiation of Th9 cells. Compared with other cytokines that can activate the NF-κB signaling pathway, IL-1β is the only factor that can effectively rescue Th9 cell differentiation under IL-2-limited conditions, and this characteristic gives it special advantages in the tumor microenvironment.

IL-1β-induced Th9 cells exert anti-tumor effects through multiple mechanisms. Firstly, IL-9 secreted by Th9 cells can directly act on tumor cells, inhibiting their proliferation and inducing apoptosis. Secondly, IL-9 can promote the recruitment and activation of mast cells, and the cytokines and chemokines released by mast cells can further recruit and activate other immune cells, such as NK cells and CTL, enhancing anti-tumor immune responses. In addition, IL-1β-induced Th9 cells highly express granzyme B and perforin, which can directly recognize and kill tumor cells. At the same time, Th9 cells can also enhance the antigen-presenting function of dendritic cells, promote the activation and proliferation of CTL, and amplify anti-tumor immune effects. These multiple mechanisms make IL-1β-induced Th9 cells a promising effector cell in tumor immunotherapy.

Ⅳ，Application Prospects and Challenges of IL-1β in Tumor Cell Therapy

Based on the key role of IL-1β in inducing Th9 cell differentiation and anti-tumor immunity, IL-1β-targeted tumor cell therapy strategies show broad application prospects. Currently, IL-1β-based cell therapy research mainly focuses on optimizing the in vitro induction protocol of Th9 cells to obtain Th9 cells with stronger anti-tumor activity for adoptive cellular immunotherapy. By adding IL-1β and IL-4 to the in vitro culture system, a large number of highly active Th9 cells can be induced, and the infusion of these cells back into tumor patients is expected to enhance anti-tumor immune responses and inhibit tumor growth.

In preclinical studies, adoptive therapy with IL-1β-induced Th9 cells has achieved significant anti-tumor effects in various tumor models. In melanoma models, adoptive therapy with IL-1β+IL-4-induced Th9 cells can significantly inhibit tumor growth and prolong the survival time of tumor-bearing mice, and its therapeutic effect is more significant compared with traditional Th9 cells. In breast cancer models, IL-1β-induced Th9 cells can effectively infiltrate into tumor tissues, directly kill tumor cells and activate endogenous immune responses by secreting IL-9 and cytotoxic molecules. These research results provide strong experimental evidence for the application of IL-1β in tumor cell therapy.

However, the application of IL-1β-related cell therapy strategies in clinical practice still faces many challenges. Firstly, the pro-inflammatory properties of IL-1β may lead to serious toxic side effects, such as systemic inflammatory response syndrome and autoimmune diseases. In the process of in vitro induction of Th9 cells, how to precisely regulate the concentration and action time of IL-1β to obtain the best anti-tumor activity while avoiding excessive inflammatory responses is a key issue to be solved. Secondly, the complexity of the tumor microenvironment may affect the survival and function of IL-1β-induced Th9 cells. Immunosuppressive factors (such as IL-10, TGF-β) and metabolites (such as lactic acid) in the tumor microenvironment may inhibit the activity of Th9 cells and reduce the therapeutic effect. Therefore, the development of combined therapy strategies, such as blocking immune checkpoint molecules (such as PD-1/PD-L1) or improving the metabolic state of the tumor microenvironment at the same time, may enhance the therapeutic effect of IL-1β-induced Th9 cells.

In addition, the dual role of IL-1β in the tumor microenvironment also increases the complexity of its clinical application. How to utilize the anti-tumor effect of IL-1β while avoiding its tumor-promoting effect requires more in-depth research to clarify the specific mechanism of IL-1β in different tumor types and different disease stages. The development of specific inhibitors or agonists targeting IL-1β to achieve precise regulation of IL-1β function may be the research direction in the future. For example, IL-1β agonists that only work locally in tumors can be designed, or IL-1β analogs that can selectively activate anti-tumor-related signaling pathways can be developed.

Ⅴ，Conclusion and Outlook

As key pro-inflammatory cytokine, IL-1β shows complex dual roles in tumor immune regulation. It is both a "sharp blade" that induces acute inflammatory responses to kill cancer cells and may become an "accomplice" that promotes tumor progression under chronic inflammatory conditions. Its unique regulatory role in Th9 cell differentiation provides new targets and strategies for tumor immunotherapy, especially the IL-1β-induced Th9 cell subset with high cytotoxicity, which shows great anti-tumor therapeutic potential. In-depth understanding of the signal transduction mechanism of IL-1β, its dual roles in the tumor microenvironment and its regulatory mechanism on Th9 cell differentiation is crucial for the development of safe and effective IL-1β-targeted tumor therapeutic strategies.

Future research should focus on the following aspects: first, further clarify the mechanism of IL-1β in different tumor types and microenvironment conditions, and identify the key regulatory factors for its tumor-promoting or anti-tumor effects; second, optimize the in vitro culture system for IL-1β-induced Th9 cell differentiation, improve the yield and anti-tumor activity of Th9 cells, and in-depth study the mechanism of their migration, survival and function maintenance in vivo; third, develop strategies for precise regulation of IL-1β function, such as tumor microenvironment-responsive IL-1β delivery systems, to achieve local precise activation of IL-1β and reduce systemic toxic side effects; fourth, explore the combined application of IL-1β-related therapies with other immunotherapeutic strategies (such as immune checkpoint inhibitors, CAR-T cell therapy), to enhance anti-tumor effects through synergistic effects.

With the in-depth understanding of the role of IL-1β in tumor immunity and the continuous development of related technologies, it is believed that IL-1β-based tumor immunotherapy strategies will be continuously improved, providing more effective and safe treatment options for tumor patients and promoting the further development of the field of tumor immunotherapy.

This article is reviewed and published by the technical expert team of UA

Disclaimer: This article partially utilizes artificial intelligence assistance in its creation. If any content involves copyright or intellectual property issues, please let us know and we promise to verify and remove it as soon as possible.

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