The dual balance of the cytokine network: key messengers of immune activation and triggers of cytokine storm.

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Introduction

Efficient intercellular communication is the fundamental principle that governs the immune system. This intricate dialogue enables the coordination of a vast network of lymphoid organs, immune cells, and soluble humoral factors—including the critical signaling proteins known as cytokines—to maintain homeostasis and defend against threats. As the core messengers of this system, cytokines were first conceptualized by Stanley Cohen in 1974 [ 1 ]. They are a class of low-molecular-weight proteins or polypeptides that are synthesized and secreted upon stimulation by immune cells, including lymphocytes, macrophages, and dendritic cells, as well as by non-immune cells such as endothelial cells, epithelial cells, and fibroblasts [ 2 ]. These molecules exist in either secreted or membrane-bound forms [ 3 ] and transmit signals between cells through autocrine, paracrine, or endocrine modes of action. Together, they form a complex network of cascading and mutually counterbalancing interactions that regulates nearly all immune responses [ 4 ] and plays an indispensable role in immune homeostasis and host defense [ 5 , 6 ].

A defining feature of this network is its binary balance, namely the dynamic equilibrium between pro-inflammatory and anti-inflammatory cytokines. Through complex positive and negative feedback loops, the cytokine network finely regulates the intensity and duration of immune responses and inflammatory processes [ 7 ]. This binary balance is of major clinical significance. Once disrupted, whether the system shifts toward excessive pro-inflammatory activity or excessive anti-inflammatory activity, it can lead to serious pathological consequences, including uncontrolled cytokine storm and profound immunosuppression [ 8 ]. Recent studies have shown that in sepsis, severe coronavirus disease 2019 (COVID-19), autoimmune diseases, and various malignancies, cytokine network imbalance is a core driver of disease onset and progression [ 9 – 11 ] (Fig. 1 ). Therefore, a deeper understanding of the homeostatic regulation of this network is of considerable theoretical and clinical importance for elucidating disease pathogenesis and developing novel immunomodulatory strategies.

Against this background, this review systematically delineates the compositional architecture, functional characteristics and canonical classification of the cytokine network, and elucidates the core mechanisms sustaining its homeostasis under physiological conditions. We subsequently focus on the hallmark manifestations of cytokine network imbalance in major pathologies including sepsis, autoimmune diseases and malignancies, dissect the intricate crosstalk between this network and inflammatory responses, and highlight the context-dependent dual roles of cytokines during immune activation. Specifically, we explore the functional duality of cytokines in the tumor microenvironment, and discuss how this intrinsic “double-edged sword” property poses both critical challenges and unprecedented opportunities for targeted therapy. We further provide a comprehensive overview of current clinical strategies targeting the cytokine network and their associated translational challenges, and elaborate on the central regulatory role of the cytokine network in immune homeostasis, the therapeutic implications of the binary balance theory, and emerging directions of immunotherapy.

Unlike conventional reviews that simply catalog cytokines by traditional pro- or anti-inflammatory labels, our core aim is to offer a nuanced, mechanistic perspective centered on the fundamental principle of cytokine functional plasticity. We highlight contexts where canonical “pro-inflammatory” cytokines exert protective/regenerative functions, while “anti-inflammatory” cytokines drive pathological progression. By framing our discussion around the context dependency of cytokine action, we make a compelling case that next-generation immunomodulatory strategies must transcend simplistic “on/off” switching, and advance toward sophisticated interventions that fully accommodate this inherent biological complexity.

Beyond a systematic summary of established cytokine biology and clinical applications of key cytokine-targeting agents, we leverage this foundational knowledge to pose a forward-looking, field-defining question: Where does the immunomodulation field go from here? We argue that, after decades of clinical success with broad-acting agents, the future of therapy lies in a granular understanding of pathway-specific pathology and the development of predictive tools. This review concludes by synthesizing these themes into a perspective on the key challenges and transformative opportunities shaping the next era of inflammatory disease treatment.

Classification and functions of cytokines

Cytokines and their functional characteristics

Cytokines are a class of low-molecular-weight proteins or glycoproteins, typically with molecular weights below 30 kDa, that possess a wide range of biological activities. Their synthesis and secretion are usually induced by immunogens, mitogens, or other biochemical stimuli [ 12 ]. Structurally, cytokines occur in diverse forms, including monomers (e.g., interferon-alpha (IFN-α)), dimers (e.g., interferon-beta (IFN-β)), and trimers (e.g., tumor necrosis factor (TNF)).

These signaling molecules are secreted by multiple cell populations, including not only key immune cells such as macrophages, lymphocytes, and mast cells, but also endothelial cells, fibroblasts, astrocytes, and various stromal cells [ 13 , 14 ]. Functionally, cytokines play indispensable roles in regulating innate immunity, adaptive immunity, hematopoiesis, cell growth and differentiation, and tissue repair. Individual cytokines exert their effects primarily through autocrine, paracrine, or endocrine signaling [ 15 , 16 ]. The mechanisms of cytokine action are highly complex and are characterized by pleiotropy, redundancy, synergy, and antagonism.

Under extreme pathological conditions, aberrant cytokine expression and uncontrolled cytokine cascades may trigger a lethal cytokine storm, leading to multiple organ dysfunction syndrome (MODS) and even death. The major cytokine families and their functional characteristics are outlined below.

Interleukins (IL)

Interleukins constitute a family of cytokines with both pro-inflammatory and anti-inflammatory immunomodulatory functions and are primarily involved in the activation and differentiation of immune cells. Historically, the term “interleukin” referred broadly to cytokines produced by leukocytes that act on other leukocytes. However, subsequent studies have shown that interleukins can be synthesized by a variety of cell types and act on a wide range of target cells. Based on structural and receptor features, interleukins are mainly classified into the IL-1 family, the common γ-chain family, the IL-10 family, and the IL-12 family, among others. To date, at least 40 interleukins have been identified (designated IL-1 to IL-40), exhibiting marked functional diversity and substantial overlap [ 17 – 19 ].

Interferons (IFN)

IFNs are a class of glycoproteins secreted in response to viral infection and other stimuli, and are mainly classified into three subtypes: IFN-α, IFN-β, and IFN-gamma (IFN-γ). Type I IFNs, including IFN-α and IFN-β, are produced primarily by innate immune cells such as macrophages, dendritic cells (DCs), and bone marrow-derived monocytes [ 20 ]. In contrast, Type II IFN (IFN-γ) is produced by a broader range of cells, including not only natural killer (NK) cells but also adaptive immune cells such as T helper 1 (Th1) cells, cytotoxic T lymphocytes, and B cells [ 21 , 22 ]. Togther, these IFNs promote immune responses and exert critical antiviral, antitumor, and immunoregulatory effects.

Tumor necrosis factors (TNF)

TNFs are a key class of pro-inflammatory cytokines and mainly include two subtypes: TNF-alpha (TNF-α) and TNF-beta (TNF-β) (also known as lymphotoxin-α, lymphotoxin-alpha (LT-α)). Among them, TNF-α is a central mediator of systemic inflammatory responses and is secreted predominantly by monocytes/macrophages. During viral infections such as influenza, dengue, and Ebola, peripheral blood TNF-α levels rise sharply. Elevated TNF-α activates T cells and induces the cascade release of downstream mediators such as IL-1, IL-6, IL-8, and IL-12, thereby triggering intense inflammatory responses, including fever and extensive macrophage recruitment [ 23 ]. Critically, the biological effects of TNF-α are governed by its existence in two functional forms: a 26-kDa membrane-bound precursor (tmTNF) and a 17-kDa soluble form (sTNF), which is released upon cleavage by the enzyme TACE (TNF-α-converting enzyme) [ 24 ]. This structural duality translates into distinct functional roles. tmTNF, acting via cell-to-cell contact (juxtacrine signaling), is a potent activator of both TNFR1 and TNFR2 receptors and is crucial for localized immune responses, such as granuloma formation for containing intracellular pathogens [ 25 , 26 ]. In contrast, sTNF acts primarily as a circulating, endocrine factor that mainly signals through TNFR1 to drive systemic inflammation [ 27 , 28 ]. During viral infections like influenza or dengue, a sharp rise in sTNF, secreted predominantly by monocytes/macrophages, is responsible for triggering systemic inflammatory responses, including fever and the cascade release of downstream mediators like IL-1 and IL-6.

Colony-stimulating factors (CSF)

Colony-stimulating factors mainly include granulocyte-macrophage colony-stimulating factor (GM-CSF), macrophage colony-stimulating factor (M-CSF), and granulocyte colony-stimulating factor (G-CSF). Their core physiological function is to stimulate the proliferation and differentiation of hematopoietic progenitor cells [ 29 ]. In addition, CSFs are important components of the pro-inflammatory network. By increasing the number of cytokine-secreting macrophages within lesions, they can sustain ongoing inflammation and promote the cascade amplification of inflammatory signaling [ 30 ].

Chemokines

Chemokines constitute a large family of low-molecular-weight cytokines (approximately 7–15 kDa). According to the arrangement of N-terminal cysteine residues, chemokines are classified into four subfamilies: CXC (e.g., the neutrophil chemoattractant C-X-C motif chemokine ligand 8 (CXCL8)), CC (e.g., monocyte chemoattractant protein C-C motif chemokine ligand 2 (CCL2)/monocyte chemoattractant protein 1 (MCP-1)), CX3C (e.g., C-X3-C motif chemokine ligand 1 (CX3CL1)), and the C subfamily (including XCL1 and XCL2) [ 31 – 33 ]. Chemokines and their receptor networks regulate the directed migration and homing of immune cells and are broadly involved in embryogenesis, immune system development, and tumor metastasis [ 34 ]. Functionally, some chemokines are pro-inflammatory and guide immune cell trafficking during inflammation, whereas others are homeostatic chemokines that help maintain tissue homeostasis and regulate basal cell migration under physiological conditions [ 35 ].

Growth factors

Growth factors are a group of polypeptides that broadly regulate cell growth, differentiation, apoptosis, and immune responses. Representative members include insulin-like growth factor (IGF), epidermal growth factor (EGF), and transforming growth factor-β (TGF-β). IGF is synthesized mainly in the liver and, in addition to its metabolic functions, promotes cell proliferation and differentiation [ 36 ]. EGF plays a central role in regulating cell migration and preserving intestinal barrier integrity [ 37 ]. Within the TGF-β family, TGF-β2 and TGF-β3 are mainly involved in embryonic development and tissue repair, whereas TGF-β1 is the most abundantly expressed isoform in the immune system. TGF-β1 exerts potent immunosuppressive effects by downregulating the expression of major histocompatibility complex (MHC) class II molecules on dendritic cells and T cells and by inhibiting immune cell proliferation and activation [ 38 ].

Classification of cytokines

Although cytokines can be grouped into different families according to molecular structure, functional classification is often more intuitive when discussing immune regulation and disease pathology. In the context of inflammation and immune homeostasis, cytokines are commonly divided into two broad categories according to their regulatory effects on inflammatory processes: pro-inflammatory cytokines and anti-inflammatory cytokines [ 39 ].

Pro-inflammatory cytokines mainly include IL-1β, IL-6, IL-8, IL-12, TNF-α, and various IFNs. During the early phase of the immune response, these mediators are rapidly released by activated innate immune cells and function as key alarm and mobilization signals. Their actions include recruiting immune cells to sites of infection, activating endothelial cells to increase vascular permeability, stimulating the liver to synthesize acute-phase proteins, and directly inducing systemic responses such as fever [ 40 , 41 ]. Together, these cascading events rapidly establish an inflammatory defense and promote pathogen clearance.

In contrast, anti-inflammatory or immunoregulatory cytokines, such as IL-4, IL-6 (context-dependent), IL-10, IL-11, IL-13, IL-1 receptor antagonist (IL-1Ra), and TGF-β, function mainly to suppress inflammation and limit excessive immune-cell activation [ 42 ]. Their key mechanisms include inhibiting the synthesis of pro-inflammatory cytokines, attenuating the activity of antigen-presenting cells, promoting the differentiation of regulatory T cells (Treg), inducing macrophage polarization toward the M2 phenotype, and facilitating tissue repair and fibrosis. Through these mechanisms, anti-inflammatory cytokines tightly constrain the intensity and duration of inflammation, thereby preventing excessive tissue injury.

In brief, pro-inflammatory cytokines drive the initiation of immune defense and autoimmune inflammation, whereas anti-inflammatory cytokines promote the resolution of inflammation and recovery from the acute phase of disease [ 43 ] (Table 1 ). Together, these molecules form a network that enables the host to maintain a dynamic balance between effective pathogen clearance and preservation of self-tolerance [ 63 ].

Dynamic balance mechanisms of the cytokine network

The cytokine network is not simply a collection of independent molecules, but a sophisticated signaling system composed of multiple cytokines and their receptors. Its physiological functions depend strongly on the local microenvironment, the metabolic state of cells, and multilayered feedback regulatory mechanisms (Fig. 2 ).

Microenvironmental specificity is a key determinant of the biological effects of cytokines. The same cytokine may induce markedly different, even opposing, biological outcomes in different microenvironmental contexts. This signaling plasticity is particularly evident in the balance between T helper 17 (Th17) and Treg differentiation. Under physiological homeostasis, TGF-β alone tends to induce expression of the transcription factor forkhead box P3 (Foxp3), thereby promoting Treg differentiation and maintaining intestinal mucosal immune tolerance. However, when pro-inflammatory signals such as IL-6 or IL-21 are present in the microenvironment, the TGF-β signaling cascade is reshaped to activate the transcription factor retinoic acid receptor-related orphan receptor gamma t (RORγt), thereby driving the differentiation of pathogenic Th17 cells [ 64 ]. This microenvironment-specific regulatory mechanism helps explain why the network may undergo adaptive shifts under certain pathological conditions, leading to the accumulation of pro-inflammatory signals. It demonstrates vividly how cytokine effects, rather than being linear, are context-dependent pathways that ultimately determine the pro-inflammatory (Th17) versus regulatory (Treg) T-cell balance which drives the inflammatory outcome.

Beyond external microenvironmental cues, the functional output of the cytokine network is also strongly regulated by the intrinsic metabolic state and epigenetic modifications of immune cells. Enhanced glycolysis generally supports pro-inflammatory phenotypes, such as M1 macrophages and Th17 cells, which are characterized by high production of effector cytokines like IL-17 [ 65 ]. In addition, pro-inflammatory factors can remodel chromatin structure—for example, by inducing histone H3K27 acetylation—thereby persistently upregulating inflammatory gene transcription. This epigenetic reprogramming allows inflammatory states to persist even after the initial stimulus has resolved [ 66 ], helping to explain why single-receptor interventions often fail to reverse established pathological networks in cancer and chronic inflammation.

At a broader physiological level, the regulatory effects of the cytokine network extend across organ systems. For example, in adipose tissue, TNF-α binds to its receptor and activates the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling pathway while reducing phosphorylation of insulin receptor substrate-1 (insulin receptor substrate 1 (IRS-1)), thereby directly converting immune-inflammatory signals into metabolic regulatory signals. This observation suggests that the cytokine network extends beyond for example, TNF-α stimulates innate immune cells like macrophages to produce IL-6. This IL-6, in turn, not only promotes its own transcription via STAT3 but, more importantly, serves as a critical signal for driving both the aforementioned Th17 cell differentiation and the terminal differentiation of B cells into antibody-secreting plasma cells [ 67 , 68 ].

To maintain the spatiotemporal dynamic homeostasis of this complex network, the immune system has evolved the classical mechanisms of positive-feedback amplification and negative-feedback braking, thereby ensuring orderly immune responses through precise threshold control. During the early stage of infection, positive feedback is used to rapidly amplify signaling and establish immune defense; for example, TNF-α induces IL-6, and IL-6 in turn promotes its own transcription via STAT3. This mechanism provides an important kinetic basis for cytokine storm. To prevent runaway inflammation, the host is equipped with multiple layers of negative regulation: cells may secrete soluble receptors or receptor antagonists, such as IL-1Ra, to block signal initiation; activation of the JAK-signal transducer and activator of transcription (STAT) pathway also induces suppressor of cytokine signaling (SOCS) proteins, which rapidly terminate activated signaling pathways [ 69 , 70 ]. During the later stages of T-cell activation, inhibitory receptors such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1) are upregulated on the T-cell surface to actively terminate immune responses. When these finely tuned counter-regulatory mechanisms collapse under pathological conditions—manifesting as uncontrolled positive feedback, impaired negative feedback, or epigenetic locking—the host may progress to severe disease states.

Cytokines and diseases

As a central regulatory hub of the immune system, the cytokine network, when dysregulated under pathological conditions, plays a key role in the initiation and progression of multiple diseases.

Cytokine imbalance in sepsis

The fundamental cause of death in sepsis is not the direct invasion of infectious agents per se, but rather severe dysregulation of the host immune response. This dysregulation triggers a devastating pathological cascade, which rapidly progresses from systemic inflammation to septic shock and multi-organ failure, and ultimately culminates in death [ 71 ]. At the core of this process is a global loss of dynamic homeostasis in the cytokine network, whereby signaling shifts catastrophically from an initially localized and controllable state to a systemic and uncontrolled inflammatory response [ 71 ].

Uncontrolled amplification of pro-inflammatory signals

During the early phase of sepsis, TNF-α levels rise sharply and trigger an inflammatory cascade centered on IL-6. At this stage, reduced ubiquitination of receptor-interacting protein kinase 1 (RIPK1) promotes necroptosis, and damage-associated molecular patterns (DAMPs) released from necrotic cells further overactivate macrophages, thereby sustaining and amplifying inflammatory signaling [ 72 ]. At the same time, lipopolysaccharide signals through TLR4, first rapidly upregulating TNF-α via the myeloid differentiation primary response 88 (MyD88) pathway and then sustaining the induction of IFN-β and IL-6 through the TIR-domain-containing adapter-inducing IFN-β (TRIF) pathway, thus creating a seamless temporal transition between the two signaling pathways [ 73 – 75 ]. Studies have shown that TLR4 blockade significantly reduces the peak levels of TNF-α and IL-6 in cardiac tissue [ 75 ]. As TNF-α levels continue to increase, the TNF receptor 1 (TNFR1)-RIPK1 complex recruits TGF-β-activated kinase 1 (TAK1)-binding protein 2 (TAB2)-TAK1 kinases, promoting nuclear translocation of NF-κB and further amplifying IL-1β expression. IL-1β then enhances NF-κB and mitogen-activated protein kinase (MAPK) activity through the IRAK4–TRAF6 pathway, whereas IL-6 prolongs its own transcription through a glycoprotein 130 (gp130)-STAT3 autocrine loop. As a result, pro-inflammatory signaling can continue in a self-sustaining manner even after the initial pathogenic stimulus has weakened [ 76 – 78 ]. Because early negative regulators such as SOCS3 are not yet sufficiently expressed at this stage, the balance between pro-inflammatory and anti-inflammatory signaling is further disrupted [ 78 – 80 ].

Once TNF-α and IFN-γ accumulate to toxic levels, RIPK1 ubiquitination is further suppressed, and its conformation shifts from complex I to complex IIb, thereby inhibiting caspase-8 activity. This switches cell death from relatively “silent” apoptosis to RIPK1/RIPK3/mixed lineage kinase domain-like protein (MLKL)-mediated pro-inflammatory necroptosis. Membrane rupture then causes massive release of DAMPs, including high-mobility group box 1 and mitochondrial DNA (mtDNA), which spread pro-inflammatory signals into surrounding tissues [ 81 ] and exponentially intensify local inflammation. At the same time, these DAMPs directly impair anti-inflammatory signaling downstream of the IL-10 receptor. Extracellular mtDNA is recognized by the NOD-like receptor protein 3 (NLRP3) inflammasome in macrophages and endothelial cells, triggering a secondary burst of IL-1β through Caspase-1 and promoting renewed secretion of IL-6 [ 82 – 84 ]. Subsequent endothelial necrosis releases additional mtDNA, creating a vicious cycle that rapidly propagates inflammation along the vascular bed. Ultimately, the platelet TLR4-NF-κB pathway and the neutrophil NLRP3 inflammasome form a transcellular interaction loop: CXCL4 induces formation of neutrophil extracellular traps (NETs), and mtDNA released from NETs in turn reactivates platelets to secrete IL-1β and IL-8 [ 85 – 87 ]. At this point, localized pro-inflammatory signaling has evolved into a systemic storm, accompanied by impaired anti-inflammatory signal transduction, marking progression to a lethal stage of systemic dysregulation. Notably, inhibition of NET formation can significantly alleviate myocardial inflammation and apoptosis in sepsis [ 88 ].

Insufficient compensation of anti-inflammatory responses

Under normal physiological conditions, once pro-inflammatory signaling reaches its peak, the host should activate a negative-feedback network centered on IL-10 and TGF-β to limit the spread of inflammation. However, the lethal pathology of sepsis lies in the profound failure of this anti-inflammatory network: not only does IL-10 decline markedly in abundance, but its signal transduction is also synchronously suppressed at post-transcriptional, epigenetic, and metabolic levels.

First, the cellular sources of IL-10 are rapidly depleted. Single-cell sequencing has shown that Foxp3 + Treg cells undergo extensive apoptosis early in the disease course, whereas the remaining Treg cells enter a state of functional exhaustion owing to persistently high PD-1 expression. This is manifested mainly by impaired nuclear translocation of NFATc2 and reduced activating H3K27ac marks at the IL-10 promoter, resulting in a precipitous decline in IL-10 secretory capacity [ 89 , 90 ]. Meanwhile, although the number of MDSCs increases compensatorily, the 3′ untranslated region (3′UTR) of IL-10 mRNA in these cells is targeted for degradation by miR-30d-5p, leading to inefficient protein translation. This state of preserved cell numbers but impaired function further depletes the effective sources of anti-inflammatory mediators [ 91 ].

A more concealed defect occurs within the post-receptor signaling axis. Under sustained exposure to intense inflammation, the JAK1–STAT3 pathway downstream of the IL-10 receptor becomes dysregulated. Inflammatory stimulation increases DNA methylation in the promoter region of the SOCS3 gene, leading to abnormally prolonged SOCS3 expression. Excess SOCS3 binds with high affinity to the JAK1 kinase domain, thereby inhibiting phosphorylation of STAT3 at Tyr705. As a result, even when IL-10 levels are increased exogenously in clinical settings, sufficient STAT3 dimers still fail to translocate to the nucleus [ 78 , 79 ]. This means that the negative-feedback loop is effectively severed at the post-receptor level, producing a state of “signal disconnect” characterized by high ligand abundance but low downstream responsiveness.

In addition, metabolic reprogramming further locks the anti-inflammatory program into an inactive state. In sepsis, AMPKα1 inactivation leads to sustained hyperactivation of mechanistic target of rapamycin complex 1 (mTORC1), forcing Treg to shift toward glycolytic metabolism. This metabolic shift depletes the intracellular acetyl-CoA pool, resulting in reduced H3K27ac at the enhancer region of the IL-10 gene and consequent chromatin compaction [ 92 ]. Under this dual metabolic and epigenetic constraint, Treg cells lose their immunosuppressive capacity and can no longer restrain the IFN-γ storm driven by CD4 + effector T cells. Taken together, the anti-inflammatory defect in sepsis is multifaceted—encompassing source depletion, post-receptor blockade, and metabolic locking—thereby driving the imbalance between pro-inflammatory and anti-inflammatory signaling from local dysregulation to systemic immune paralysis (Fig. 3 ).

Cytokine imbalance in psoriasis

The pathological core of psoriasis lies in the immune system’s persistent aberrant recognition of self-antigens. Unlike the abrupt systemic collapse observed in sepsis, psoriasis manifests as a chronic, tissue-specific autoimmune inflammatory state. Its characteristic imbalance is marked by abnormal and sustained activation of the IL-23/IL-17-centered pro-inflammatory axis, together with insufficient functional compensation by regulatory cytokines such as IL-10. These processes jointly drive persistent inflammatory hyperplasia and remodeling of the skin barrier.

Abnormal persistent activation of the IL-23/IL-17 axis

In psoriatic lesions, antigen-presenting cells secrete excessive amounts of IL-23. By activating the STAT3 signaling pathway, IL-23 potently drives the differentiation of naïve CD4 + T cells into the Th17 lineage [ 93 ], which subsequently produce large amounts of IL-17A, IL-17F, and IL-22, thereby initiating a cascade of cutaneous inflammation [ 51 , 53 ]. When IL-23 remains persistently elevated in the local microenvironment, the intracellular E3 ubiquitin ligase Nedd4 becomes inactivated, impairing ubiquitin-mediated degradation of RORγt, the master transcription factor of Th17 cells. As a result, RORγt accumulates abnormally and remains highly stable, leading to sustained enhancement of its transcriptional activity [ 53 , 94 ]. Single-cell sequencing further shows that, in T cells at the margins of lesions, increased IL-17A mRNA stability coincides with enhanced skin-homing capacity, a key mechanism underlying the local amplification and persistence of inflammation. The large amounts of IL-17A produced then act on keratinocytes, inhibiting terminal differentiation, promoting hyperproliferation, and inducing the release of antimicrobial peptides and multiple chemokines [ 95 ]. These chemokines recruit large numbers of neutrophils into the epidermis, where they form characteristic microabscesses, and further attract other immune cells to infiltrate the dermis, thereby establishing a self-amplifying positive-feedback loop [ 96 ].

Under sustained IL-23 stimulation, prolonged STAT3 phosphorylation drives T cells into an irreversible state of persistent activation. Specifically, the mTORC1-hypoxia-inducible factor 1-alpha (HIF-1α) metabolic axis upregulates pyruvate kinase M2, leading to marked intracellular lactate accumulation, and autocrine lactate signaling further stabilizes RORγt expression [ 97 ]. At the same time, increased H3K27ac at the Runx3 promoter epigenetically locks these cells into a tissue-resident memory T-cell (tissue-resident memory T cell (TRM)) phenotype. These stabilized Th17/TRM cells then secrete GM-CSF, recruit CCR2 + Ly6C h i pathogenic monocytes, and drive the spread of inflammation from individual lesions to broader tissue regions, thereby establishing a chronic self-sustaining cycle across tissues [ 53 , 91 , 98 ].

Functional defects in regulatory factors such as IL-10

Under suppression by the dominant IL-23/IL-17 pro-inflammatory network, the endogenous anti-inflammatory regulatory system centered on IL-10 and TGF-β becomes overwhelmed and functionally impaired. Foxp3 + Treg cells are highly prone to apoptosis in the psoriatic inflammatory microenvironment, whereas surviving Treg cells enter a state of functional inhibition because of high PD-1 expression, as reflected by impaired NFATc2 nuclear translocation and reduced H3K27ac at the IL-10 promoter [ 99 ], ultimately leading to markedly decreased IL-10 secretion [ 89 ]. Similar to sepsis, expanded MDSCs also lose immunosuppressive function because IL-10 mRNA is degraded by miR-30d-5p. At the signaling level, chronic intense inflammation induces DNA methylation of the SOCS3 promoter, leading to SOCS3 overexpression. This inhibits activation of the JAK1–STAT3 pathway at the post-receptor level, preventing both exogenous and endogenous IL-10 from effectively transmitting anti-inflammatory signals [ 78 – 80 ].

At the level of metabolic reprogramming, AMPKα1 inactivation together with excessive mTORC1 activation similarly drives Treg cells toward glycolytic metabolism. The resulting depletion of acetyl-CoA causes chromatin compaction at the enhancer region of the IL-10 gene, thereby epigenetically locking the anti-inflammatory transcriptional program [ 92 , 100 ]. More distinctively, under normal physiological conditions, Treg cells maintain peripheral tolerance by CTLA-4-mediated trans-endocytosis of CD80/86 from antigen-presenting cells. In psoriasis, however, stressed keratinocytes release large amounts of ULBP4, which excessively activates NKG2D on Treg cells and promotes internalization of the inhibitory phosphatase Src homology region 2 domain-containing phosphatase 1 (SHP-1). This process directly disrupts CTLA-4-mediated inhibitory signaling. Although Treg-cell numbers may appear preserved, their actual immunosuppressive function is profoundly exhausted [ 76 ]. Taken together, the anti-inflammatory defect in psoriasis represents a comprehensive multilevel failure involving impaired cytokine production, defective signal transduction, and metabolic-epigenetic dysregulation (Fig. 4 ).

Cytokine imbalance in tumors

Within the TME, cytokine network imbalance manifests as a highly insidious, chronic, and progressively reprogrammed state. Its core pathological feature is an aberrant synergy between pro-inflammatory signals, such as IL-6, and immunosuppressive signals, such as TGF-β and IL-10, which together establish and maintain a microenvironment favorable for tumor immune evasion and progression [ 101 ]. This imbalance ultimately leads to profound impairment of host antitumor immune surveillance.

Synergistic formation of pro-inflammatory and immunosuppressive networks

During the early stages of tumorigenesis, high levels of IL-6 begin to accumulate persistently within the TME, produced jointly by tumor cells, CAFs, and infiltrating myeloid cells. Upon binding to its receptor gp130, IL-6 potently activates the downstream JAK-STAT3 signaling pathway. This not only directly promotes tumor-cell proliferation and resistance to apoptosis, but also feeds back through STAT3 to increase IL-6 transcription in CAFs and myeloid cells, thereby forming a powerful positive-feedback loop [ 78 , 102 ]. In addition, certain epigenetic modifications markedly prolong the half-life of IL-6 mRNA, allowing this pro-inflammatory signal to persist and dominate the immune landscape of the microenvironment even after the initial stimulus has subsided.

The chronic inflammatory milieu shaped by IL-6 provides a favorable context for the accumulation and pathological action of TGF-β. Once TGF-β reaches a critical threshold, it strongly drives cancer-associated fibroblast (CAF) activation and induces epithelial-mesenchymal transition in tumor cells through the Smad2/3 pathway, thereby remodeling a profibrotic stroma and markedly enhancing tumor invasiveness [ 103 ]. In the context of immune regulation, TGF-β directly and potently suppresses the cytotoxic functions of cytotoxic T lymphocytes and NK cells while inducing expansion of Treg, thereby establishing a robust immunosuppressive barrier within the TME [ 104 ].

More importantly, IL-6 and TGF-β engage in pathological synergy. Together, they upregulate GM-CSF expression, recruit large numbers of Ly6C h i monocytes into tumors, and polarize them into M2-like TAMs with strong immunosuppressive activity [ 104 ]. In addition, TGF-β can induce senescence in tumor vascular endothelial cells, causing them to release a senescence-associated secretory phenotype enriched in IL-6 and IL-8. These SASP factors program infiltrating neutrophils toward a protumor N2 phenotype and promote NET formation. Under normal circumstances, the double-stranded DNA released by NETs would be expected to activate the antitumor cyclic GMP-AMP synthase (cGAS)-stimulator of IFN genes (STING) pathway; however, in the remodeled TME, the output of this pathway is pathologically reprogrammed, shifting from production of type I IFNs toward secretion of immunosuppressive mediators such as IL-10 and pro-angiogenic factors such as vascular endothelial growth factor (VEGF) [ 85 , 104 , 105 ]. Thus, a closed pathological circuit is established within the TME: pro-inflammation → immunosuppression → stromal senescence → N2 neutrophils → immune evasion and angiogenesis. In this way, the pro-inflammatory and immunosuppressive networks become tightly integrated and self-sustaining.

Synchronous dysregulation of effector and regulatory signals

In a highly evolved TME, regulatory signaling exhibits a paradoxical pattern of high expression but low responsiveness. Although IL-10 expression is often markedly elevated, its anti-inflammatory signal transduction is severely impaired. Prolonged exposure to high IL-6 levels induces strong SOCS3 expression in TME cells, and SOCS3 competitively binds JAK1, thereby blocking STAT3 phosphorylation and nuclear translocation [ 78 , 79 , 106 ]. At the epigenetic level, factors such as TGF-β erase activating histone marks at the enhancer region of the IL-10 gene through the JMJD6–STAT3 axis, thereby locking down its effective anti-inflammatory program at the transcriptional level [ 78 ]. As a result, IL-10 loses its ability to restrain local inflammation while largely retaining its suppressive effects on effector T cells.

At the same time, effector signals responsible for tumor killing are also subject to pathological counter-regulation. IFN-γ secreted by infiltrating cytotoxic T cells is a key antitumor effector molecule. However, within the regulatory context of the TME, IFN-γ not only activates immunity but also strongly induces programmed death-ligand 1 (PD-L1) expression on tumor cells and stromal cells. This creates a lethal negative-feedback loop: the more IFN-γ is produced by T cells, the more abundant PD-L1 becomes in the microenvironment, which in turn accelerates T-cell dysfunction and exhaustion through PD-1 signaling [ 104 , 107 ]. Ultimately, the cytokine network in the TME enters a state of global dysregulation, in which pro-inflammatory signals are hijacked to remodel the stroma, regulatory signals such as IL-10 lose their anti-inflammatory function, and effector signals such as IFN-γ paradoxically promote immune exhaustion (Fig. 5 ).

Cytokine imbalance in rheumatoid arthritis

The pathological basis of rheumatoid arthritis lies in persistent cytokine network imbalance within the synovial microenvironment, together with the progressive destruction of cartilage and bone driven by this imbalance. Within the relatively enclosed joint cavity, key pro-inflammatory cytokines such as TNF-α, IL-6, and IL-17A form a powerful synergistic network. This network not only sustains chronic autoimmune inflammation, but also drives synovial fibroblasts toward an invasive tumor-like phenotype and promotes osteoclast activation. Alongside this process, negative regulatory mechanisms such as those mediated by IL-10 become broadly impaired, ultimately converting immune dysregulation into irreversible structural joint damage.

Synergistic pathogenesis of TNF-α/IL-6/IL-17

Triggered by unknown endogenous antigens or alarmins, synovial-resident macrophages and fibroblast-like synoviocytes continuously activate the NF-κB pathway through pattern-recognition receptors, resulting in abnormally high early expression of TNF-α transcripts [ 108 ]. This process is accompanied by rapid phosphorylation and degradation of the inhibitory protein IκBα, thereby releasing the constraint on nuclear translocation of the NF-κB p65 subunit. The large amounts of TNF-α released then bind TNFR1 in both autocrine and paracrine fashion. On the one hand, TNF-α induces high expression of adhesion molecules such as vascular cell adhesion molecule 1 (VCAM-1) and intercellular adhesion molecule 1 (ICAM-1) on local vascular endothelial cells, thereby promoting massive recruitment of lymphocytes and neutrophils into the joint cavity. On the other hand, TNF-α directly stimulates synoviocytes to secrete large amounts of IL-1β and IL-6, shifting the local homeostatic balance toward a strongly pro-inflammatory state from the early phase of disease [ 79 , 109 ].

As TNF-α signaling becomes established, IL-6 emerges as a key hub in amplifying inflammation. Upon binding to gp130, IL-6 potently activates the JAK-STAT3 pathway. This not only prolongs the survival of synoviocytes and confers resistance to apoptosis, but also directly upregulates expression of receptor activator of NF-κB ligand through STAT3 and drives the synthesis of multiple matrix metalloproteinases, including matrix metalloproteinase (MMP)-1 and MMP-3 [ 110 ], thereby initiating cartilage matrix degradation [ 78 , 79 ]. Subsequently, IL-23-driven Th17 cells migrate into the synovium and release large amounts of IL-17A. Through the Act1-TRAF6 axis, IL-17A activates both MAPK and NF-κB signaling, and by stabilizing RORγt, further stimulates synoviocytes and chondrocytes to produce the more destructive enzymes MMP-13 and ADAMTS-4 [ 96 , 111 ]. As a result, a highly synergistic positive-feedback loop of IL-6 → IL-17A → receptor activator of nuclear factor kappa-B ligand (RANKL)/MMP is established within the joint cavity. Importantly, fragments of type II collagen and aggrecan generated by proteolytic cleavage are captured by local antigen-presenting cells as neo-autoantigens, which in turn activate additional autoreactive Th17 cells [ 112 ]. This self-amplifying loop—where antigens drive inflammation, inflammation induces tissue-destructive enzymes, and tissue destruction releases new antigens—allows rheumatoid arthritis to continue progressing even after the initial trigger has receded [ 79 , 89 ].

The ultimate consequence of this pathogenic network is structural collapse at the cartilage-bone interface. High levels of RANKL bind to RANK on osteoclast precursors, activate NFATc1 signaling, and drive extensive osteoclast differentiation and activation, resulting in broad subchondral bone erosion. Meanwhile, MMP-mediated cartilage degradation exposes cryptic epitopes, activates the complement system, and promotes formation of the membrane attack complex, thereby inflicting further injury on chondrocytes. Under prolonged exposure to this cytokine-rich inflammatory environment, synoviocytes ultimately acquire an invasive phenotype resembling that of malignant cells, characterized by uncontrolled proliferation and formation of a destructive pannus over the bone surface. This enables inflammation to extend beyond the synovium and directly erode cortical bone, ultimately leading to severe joint deformity and loss of function.

Suppression of anti-inflammatory and repair pathways

Under suppression by the overwhelming pro-inflammatory network, the IL-10-centered regulatory axis becomes impaired at three key levels: cytokine production, signal transduction, and cellular effector function. First, the source of IL-10 production is profoundly altered. The extremely high concentration of TNF-α within the synovial cavity activates TNF receptor 2 (TNFR2) signaling and severely destabilizes Foxp3 transcripts in Treg cells, promoting their ubiquitination and degradation. As a result, many Treg cells not only lose their immunosuppressive function but instead convert into inflammatory effector T cells that secrete IFN-γ [ 89 ]. Second, IL-10 receptor signaling is effectively blocked. Sustained high IL-6 activates STAT3 and induces hypermethylation of the SOCS3 promoter, leading to excessive and persistent SOCS3 expression. SOCS3 binds tightly to the JAK1 kinase domain associated with the IL-10 receptor and inhibits STAT3 activation [ 113 ]. Consequently, even when IL-10 is present in the synovium, its anti-inflammatory signal cannot be effectively transmitted to the nucleus, resulting in a state of “signal blockade”.

Beyond IL-10, other endogenous protective mechanisms are also disrupted. For example, endogenous type I IFN, which normally suppresses MMP synthesis, while also performing critical immunomodulatory functions such as promoting Th1 differentiation and regulating B cell responses, has its production pathway blocked by IL-1β. SOCS1 induced by IL-1β targets phosphorylated IRF3 for degradation, thereby prematurely terminating IFN-β synthesis [ 76 , 77 ]. At the same time, within the unique inflammatory milieu of the rheumatoid arthritis (RA) synovium, TGF-β signaling becomes distorted: instead of promoting Treg differentiation, it acts together with IL-6 to facilitate differentiation of pathogenic Th17 cells [ 89 ]. In short, cytokine imbalance in RA reflects not only excessive pro-inflammatory activity but also broad failure of endogenous braking systems. This failure manifests at the cellular level as a disrupted T cell landscape, characterized by the diminished protective capacity of IFN-β and the skewed differentiation away from Tregs and towards pathogenic Th17 cells, driven by the distorted TGF-β signaling (Fig. 6 ).

Cytokine imbalance in inflammatory bowel disease

The pathological basis of inflammatory bowel disease lies in a vicious interaction between defects in the intestinal mucosal barrier and persistent stimulation by commensal microbiota. Excessive immune responses of the intestinal mucosal immune system to microbial antigens trigger a pro-inflammatory network centered on TNF-α and the IL-23/IL-17 axis. This network directly damages the intestinal epithelial barrier, while barrier disruption in turn further increases leakage of microbial products, thereby creating a difficult-to-break self-sustaining inflammatory cycle. At the same time, mucosal immune tolerance mechanisms represented by IL-10 undergo failure at multiple levels, jointly driving the transition from local acute inflammation to chronic inflammation and irreversible intestinal fibrosis.

Abnormal activation of TNF-α and the IL-23/IL-17 axis

In genetically susceptible individuals, minor defects in the intestinal physical barrier allow products derived from commensal microbiota to continuously penetrate into the lamina propria. These products repeatedly activate resident macrophages and dendritic cells through the Toll-like receptor (TLR)-NF-κB pathway, thereby driving persistent high-level expression of TNF-α [ 114 ]. The resulting increase in TNF-α serves as a key upstream inflammatory signal: it upregulates endothelial adhesion molecules to recruit large numbers of lymphocytes and neutrophils, while also acting in an autocrine manner to stimulate antigen-presenting cells to secrete large amounts of IL-12 and IL-23 [ 91 , 115 ]. IL-12 then promotes Th1 differentiation and IFN-γ production through STAT4, whereas IL-23 stabilizes RORγt via STAT3, strongly driving Th17 differentiation and release of IL-17A [ 91 , 116 , 117 ]. Together, IFN-γ and IL-17A profoundly disrupt the immune-tolerant microenvironment of the intestine.

Within this inflammatory process, IL-17A plays a pivotal destructive role. It directly inhibits synthesis of intestinal epithelial tight junction proteins and induces epithelial cells to release chemokines, thereby exacerbating the vicious cycle of bacterial translocation and inflammatory recruitment. At the same time, IL-17A induces epithelial cells to produce large amounts of reactive oxygen species, which rapidly activate the NLRP3 inflammasome and promote maturation and release of IL-1β [ 91 , 118 , 119 ]. IL-1β then further enhances IL-23 production, thereby establishing a closed positive-feedback loop in the intestinal mucosa: IL-23 → IL-17A → reactive oxygen species (ROS) → IL-1β → IL-23. This circuit allows intestinal inflammation to persist in a self-sustaining manner even after the initial bacterial trigger has weakened. Long-term exposure to such an inflammatory milieu also drives pathogenic phenotypic conversion of intestinal fibroblasts: sustained STAT3 phosphorylation upregulates the transcription factor Runx2, while H3K27ac at profibrotic collagen gene regions increases significantly. This promotes collagen deposition, VEGF overexpression, and abnormal angiogenesis, ultimately driving destructive fibrosis of the intestinal wall. The transformed stromal cells can in turn secrete IL-6 and GM-CSF, thereby sustaining the survival of Th17 cells and pathogenic monocytes and driving inflammation from the superficial mucosa into the deeper muscular and serosal layers.

In addition, IL-17A exerts multiple tissue-destructive effects. It upregulates transcription of MMP-9 and MMP-3, directly degrading type IV collagen and laminin in the basement membrane [ 60 ]. The disrupted basement membrane not only loses its barrier function, but its fragments are also taken up by dendritic cells, which further stimulate IL-23 expression through the TLR2-MyD88 pathway and thereby reinforce Th17 polarization [ 56 , 114 ]. IL-17A also induces severe endoplasmic reticulum stress in intestinal epithelial cells by activating the PERK-eIF2α-CHOP axis, which impairs synthesis of the protective mucin MUC2, thins the mucus layer, and markedly increases penetration of microbial products. Finally, IL-17A directly induces IL-36γ expression, and IL-36γ in turn acts on the Syk-phosphoinositide 3-kinase (PI3K) pathway in macrophages, forming an additional positive-feedback branch that promotes co-expression of IL-1β and IL-23.

Widespread failure of multilevel immune regulation

Within the strongly pro-inflammatory TNF-α/IL-12 environment, Foxp3 + Treg cells responsible for maintaining intestinal immune tolerance become highly vulnerable and prone to apoptosis. The remaining Treg cells enter a state of profound exhaustion due to the high expression of inhibitory receptors such as PD-1, resulting in a marked decline in IL-10 production [ 116 , 120 ]. Even when MDSCs expand compensatorily, impaired IL-10 mRNA stability and translational efficiency prevent them from filling the functional gap left by Treg cells. As in the diseases discussed above, the inflammatory milieu in inflammatory bowel disease (IBD) also induces sustained SOCS3 overexpression, which inhibits the JAK1–STAT3 pathway and paralyses post-receptor signal transduction [ 121 ]. Consequently, the residual IL-10 that remains is functionally ineffective.

A further complication is that, in a microenvironment rich in both IL-6 and ROS, ROS directly oxidatively modifies Smad3, a downstream mediator of TGF-β signaling. This modification alters the DNA-binding specificity of Smad3, markedly increasing its affinity for the RORγt promoter while sharply reducing its affinity for the Foxp3 promoter. As a result, the functional role of TGF-β is dramatically shifted—from a factor that normally promotes Treg differentiation to a pro-inflammatory cofactor that cooperates with IL-6 to drive Th17 differentiation [ 60 , 76 , 122 ]. In addition, metabolic reprogramming, characterized by reduced AMP-activated protein kinase (AMPK) activity and elevated mTORC1 activity, forces Treg cells toward glycolysis; the resulting depletion of acetyl-CoA causes chromatin compaction at the enhancer region of the IL-10 gene [ 92 ]. Together, these metabolic and epigenetic locking mechanisms lead to profound loss of intestinal immune tolerance (Fig. 7 ).

A detailed comparison of the pathological mechanisms underlying sepsis, psoriasis, tumors, RA, and IBD reveals that cytokine network imbalance follows a strikingly similar trajectory across these otherwise distinct disorders (Table 2 ). In each case, abnormal escalation of pro-inflammatory cytokines occurs in parallel with multidimensional failure of the anti-inflammatory network. Positive-feedback amplification gradually overrides the original bidirectional counter-regulatory mechanisms, eventually allowing inflammation to become detached from its initiating triggers, such as infection or self-antigens, and to evolve into a self-sustaining pathogenic driver. Specifically, pro-inflammatory cytokines represented by TNF-α, IL-6, IL-23, and IL-17 maintain high-level signaling through core pathways such as JAK-STAT and NF-κB, while also fundamentally reshaping target-cell phenotypes through epigenetic and metabolic reprogramming [ 53 ]. In parallel, the regulatory system centered on IL-10 and TGF-β is suppressed at multiple levels, including impaired production, post-transcriptional degradation, SOCS-mediated blockade of receptor signaling, and DNA methylation-mediated epigenetic silencing [ 89 ]. Once such a severely skewed network becomes stabilized, single-target inhibition or simple cytokine supplementation is often insufficient and may even trigger compensatory bypass mechanisms. Therefore, the strategic goal of modern immunomodulatory therapy should shift from static single-node inhibition toward coordinated restoration of multiple key processes within critical therapeutic windows, including cytokine production, signal transduction, and epigenetic reprogramming, so as to rebuild the dynamic balance of positive and negative feedback within the cytokine network [ 104 , 134 , 135 ].

Cytokine network and inflammatory responses

Roles of cytokines in acute and chronic inflammation

Inflammation is a protective physiological response mounted by the host against tissue injury, toxic chemicals, or invading pathogens [ 136 ]. It is fundamentally a highly complex immunological cascade that aims to eliminate harmful stimuli and ultimately repair damaged tissue through the coordinated recruitment of immune cells and the release of vasoactive peptides, pro-inflammatory cytokines, lipid mediators such as eicosanoids, and acute-phase proteins. In this process, cytokines function as central regulators of inflammation and play decisive roles in intercellular communication, inflammatory initiation, signal amplification, and subsequent resolution.

Acute inflammation is typically characterized by rapid onset, short duration, and marked vascular responses. During this phase, cytokines primarily serve alarm and mobilization functions. Upon pathogen invasion, tissue-resident macrophages and mast cells recognize pathogen-associated molecular patterns (PAMPs) through TLRs, thereby rapidly secreting TNF-α and IL-1β [ 137 ]. These early pro-inflammatory cytokines upregulate adhesion molecules such as selectins and integrins on vascular endothelial cells, promoting neutrophil margination and transendothelial migration into sites of inflammation [ 138 ]. Pro-inflammatory cytokines then activate surrounding immune cells through autocrine and paracrine signaling, leading to cascade amplification. For example, IL-1β induces IL-6 production in target cells, and circulating IL-6 stimulates the liver to synthesize acute-phase proteins such as C-reactive protein, thereby enhancing phagocyte opsonic activity and complement activation and further amplifying pathogen clearance [ 139 ]. Once the pathogenic insult has been eliminated, the network shifts toward an anti-inflammatory phenotype. Anti-inflammatory cytokines, especially IL-10 and TGF-β, then become dominant and promote resolution of inflammation by suppressing pro-inflammatory signaling pathways [ 140 ]. However, if the balance between pro-inflammatory and anti-inflammatory signals is disrupted, severe cytokine storm may develop, leading to excessive vascular permeability, hemodynamic instability, and even fatal systemic complications such as acute respiratory distress syndrome (ARDS) [ 141 ].

Chronic inflammation arises when acute inflammation fails to eliminate pathogens effectively or when harmful stimuli persist over time [ 142 ]. Its main histological features include sustained infiltration of mononuclear cells, macrophages, and lymphocytes, often accompanied by progressive tissue destruction and aberrant repair in the form of fibrosis [ 143 ]. During the chronic phase, cytokine secretion shifts from the burst-like pattern seen in acute inflammation to sustained production [ 144 ] (84). Stable cellular interaction loops are established within the microenvironment: activated T cells continuously secrete IFN-γ to maintain macrophages in a highly activated state, whereas activated macrophages in turn produce IL-12 to sustain T-cell responses [ 145 ]. This bidirectional positive-feedback loop underlies dense lymphocyte accumulation at inflammatory sites and granuloma formation. In later stages of chronic inflammation, TGF-β assumes a particularly important pathogenic role. Although it has baseline immunosuppressive effects, prolonged overexpression drives persistent fibroblast proliferation and excessive extracellular matrix (ECM) deposition, ultimately leading to irreversible tissue remodeling and organ fibrosis, such as airway remodeling in chronic obstructive pulmonary disease or cirrhosis caused by chronic hepatitis [ 146 ]. In addition, chronic low-grade systemic inflammation, such as persistent elevation of circulating IL-6, can interfere with insulin signaling and disrupt lipid metabolism, thereby contributing to metabolic syndromes such as obesity, type 2 diabetes, and cardiovascular disease [ 147 ].

Mechanisms of cytokine storm

Whether triggered by severe infection, autoimmune disease, malignancy, certain genetic defects, or iatrogenic interventions such as CAR-T-cell therapy, the host may develop a life-threatening systemic inflammatory syndrome. Its pathological core lies in extreme immune-cell activation and uncontrolled massive cytokine release. Once inflammatory responses exceed physiological regulatory thresholds, they rapidly self-amplify through positive-feedback loops. Clinically, this process initially manifests as cytokine release syndrome (CRS) [ 148 ], and when it progresses to severe organ dysfunction, it is defined as cytokine storm (CS) [ 149 ].

The essence of CS is the complete breakdown of immune binary homeostasis. Although the host attempts to activate compensatory anti-inflammatory mechanisms, the overwhelming strength of pro-inflammatory signaling exceeds the buffering capacity of the regulatory network. The pathological process usually begins at a local site and then rapidly spreads into the systemic circulation. Within a short period, nonspecific flu-like symptoms such as fever, myalgia, and fatigue may progress to MODS [ 10 , 150 – 153 ]. This catastrophic amplification process involves highly complex network interactions, and its core mechanisms can be understood across several key dimensions.

IFN-γ secreted by activated T cells and NK cells is a potent activator of macrophages and serves as an upstream igniting signal in the inflammatory cascade. At the same time, the IL-1 family also functions as a critical initiating driver. IL-1α and IL-1β, encoded by the IL1A and IL1B genes, respectively, bind to the shared IL-1 receptor and potently activate core intracellular pathways such as NF-κB, thereby broadly initiating transcription of downstream pro-inflammatory genes. The initial burst of these cytokines provides the momentum for the subsequent development of systemic inflammatory storm.

IL-6 is the central effector mediator and pathological amplifier in CS. Marked elevation of IL-6 is consistently observed in severe immunopathological disorders [ 154 , 155 ] and in animal models of CS [ 156 ]. IL-6 acts through two distinct mechanisms [ 46 ]. First, in cis-signaling mediated by the membrane-bound IL-6 receptor, IL-6 binds mIL-6 R and gp130 to regulate the functions of classical immune cells such as T cells, B cells, and macrophages. Second, the mechanism primarily responsible for widespread tissue injury is trans-signaling. During CS, very high levels of circulating IL-6 bind soluble IL-6 receptor, forming a highly active complex. Because gp130 is expressed on a wide range of cell types, including vascular endothelial cells that do not normally express mIL-6 R, this complex can activate gp130 on endothelial cells and trigger downstream pathways including JAK-STAT3, protein kinase B (Akt)-mechanistic target of rapamycin (mTOR), and MAPK-extracellular signal-regulated kinase (ERK). This trans-signaling drives systemic inflammation by inducing endothelial cells to secrete large amounts of MCP-1, IL-8, and additional IL-6, thereby establishing a strong positive-feedback loop. More importantly, it markedly increases VEGF expression and reduces E-cadherin expression, directly compromising endothelial barrier integrity and leading to widespread vascular leakage, refractory hypotension, and acute pulmonary dysfunction [ 46 ].

TNF, especially TNF-α, is a key initiating mediator of tissue necrosis and circulatory failure. Under extreme pathological conditions, its major pathogenic effect extends beyond normal host defense and is closely related to excessive activation of the NF-κB pathway. Through this pathway, TNF-α not only induces broad pro-inflammatory gene expression but also directly promotes extensive cell death. In bacterial toxin-induced shock models, TNF-α has been identified as a central mediator of circulatory failure and MODS [ 157 ].

At the same time, intracellular inflammasomes are activated by pathogen- or damage-associated signals, leading Caspase-1 to cleave and release highly active IL-18 [ 158 – 160 ]. This process further escalates CS. IL-18 acts synergistically with IL-12 to stimulate T cells and NK cells to produce large amounts of IFN-γ, and the resulting high IFN-γ levels in turn further polarize and activate macrophages. In this way, a destructive positive-feedback loop is established—IFN-γ → activated macrophages → IL-18/IL-6 release → more IFN-γ—driving the storm toward loss of control [ 54 ].

At the peak of CS, the host attempts a final compensatory response by releasing negative regulatory molecules such as IL-10, IL-1Ra, and IL-18-binding protein (IL-18-binding protein (IL-18BP)) [ 161 ]. However, this anti-inflammatory response is insufficient to counterbalance the overwhelming pro-inflammatory burden. Moreover, excessive cytokine release further aberrantly activates the complement system, including the anaphylatoxins C3a and C5a. Cytokines and complement then engage in mutually reinforcing crosstalk, which leads to severe bystander tissue injury. In severe CS, hypocomplementemia is frequently observed clinically, largely because immune-complex formation consumes large amounts of complement [ 162 ].

In summary, CS is a multistage, cross-system form of immune dysregulation. It begins with upstream initiating factors such as IL-1 and IFN-γ, is progressively intensified through inflammasome activation and positive-feedback circuits such as the IL-18/IFN-γ loop, and ultimately extends from local inflammation to systemic vascular and parenchymal tissue injury through IL-6 trans-signaling, leading to widespread breakdown of physiological defense mechanisms (Fig. 8 ).

Dual roles of cytokines in immune activation

Pro-inflammatory roles

Inflammation is a core mechanism of host immune defense and is tightly regulated by the cytokine network. Among these mediators, pro-inflammatory cytokines act primarily as positive drivers by initiating acute-phase responses that protect the host against external stimuli, injury, and infection. This defensive program depends on the rapid release of pro-inflammatory cytokines such as IL-1β, IL-6, IL-8, IL-12, IFN-γ, and TNF-α, which may be secreted by one or multiple cell types. The principal role of pro-inflammatory cytokines is to transmit danger signals to surrounding tissues and thereby activate immune defense mechanisms. In addition, these mediators can enter the circulation and induce broad immune-cell activation together with systemic physiological changes such as fever and the acute-phase response [ 42 ].

Through multiple coordinated mechanisms, pro-inflammatory cytokines promote the activation and proliferation of immune cells, thereby establishing a robust immune barrier against invasion by exogenous pathogens such as bacteria and other microorganisms, as well as against inappropriate translocation of endogenous commensal microbiota from sites such as the skin and intestine [ 163 ]. As a first line of defense against pathogen invasion, resident macrophages play a pivotal role in initiating adaptive immune responses. Upon stimulation by bacterial products and other antigens, macrophages rapidly release multiple pro-inflammatory cytokines, including IL-1, IL-6, IL-8, IL-12, IL-18, IFN-α, IFN-γ, and TNF-α, thereby coordinating local immune defense [ 164 ].

Specifically, IL-1 exhibits direct growth-inhibitory and cytotoxic activity in vitro and enhances overall immune responses in vivo. Mechanistically, it acts as a “co-stimulatory” signal for T cells, lowering their activation threshold, and synergizes with other cytokines to drive pro-inflammatory T cell differentiation [ 165 , 166 ]. IL-6 serves as a central amplifier of inflammation. In the adaptive immune system, it plays a dual, pivotal role: it is essential for the terminal differentiation of B cells into antibody-secreting plasma cells, and, as mentioned earlier, it collaborates with TGF-β to drive the differentiation of pathogenic Th17 cells, thus linking innate signals to both humoral and cellular inflammatory pathways [ 167 , 168 ]. IL-12 is the master regulator of Type 1 immunity, markedly enhancing T-cell responsiveness and driving quiescent naive T cells to differentiate into IFN-γ-producing Th1 cells, while also activating NK cells [ 169 ]. Members of the IFN family, particularly IFN-γ, are central to cell-mediated immunity. Beyond enhancing macrophage functions and upregulating MHC expression, IFN-γ (produced mainly by the aforementioned Th1 cells) further stabilizes the Th1 lineage and inhibits the development of opposing Th2 and Th17 cells, thereby cementing a Type 1 inflammatory microenvironment [ 170 , 171 ]. These cytokines do not act in isolation; rather, they form a highly interconnected regulatory network. Released coordinately by activated immune cells, they amplify immune signaling through positive-feedback loops and synergistic interactions, thereby protecting the host against pathogen invasion.

However, pro-inflammatory responses also exemplify the biological principle of “binary balance”. Moderate production of pro-inflammatory signals is essential for pathogen clearance, tissue repair, and initiation of adaptive immunity. In contrast, excessively intense or prolonged pro-inflammatory responses disrupt systemic homeostasis and promote chronic inflammation. Chronic inflammation is closely associated with a wide range of adverse health outcomes and has been implicated in the pathogenesis of malignancy [ 172 ], diabetes [ 173 ], cardiovascular disease [ 174 ], gastrointestinal disorders [ 175 ], Parkinson’s disease [ 176 ], and age-related syndromes [ 177 ]. Therefore, precise control of the intensity and duration of pro-inflammatory responses is essential, and maintenance of dynamic immune balance is critical for preventing pathological cytokine overactivation (Fig. 9 ).

Anti-inflammatory roles

To counterbalance the pro-inflammatory network, the immune system has evolved a sophisticated negative regulatory system. This system is composed mainly of anti-inflammatory and immunoregulatory mediators, including IL-1 receptor antagonist, IL-4, IL-6, IL-10, IL-11, IL-13, and TGF-β, whose principal function is to suppress excessive expression of pro-inflammatory cytokines and prevent inflammatory cascades from becoming uncontrolled [ 45 ]. Among them, IL-10 is the prototypical anti-inflammatory cytokine. It exerts strong immunosuppressive effects by markedly inhibiting the production of pro-inflammatory cytokines from innate cells like macrophages [ 178 ]. Furthermore, it directly acts on T cells to suppress their proliferation and effector functions, and on B cells to modulate antibody production, serving as a critical brake on adaptive immune responses [ 179 , 180 ]. IL-10 also directly suppresses eosinophils, basophils, and mast cells, and therefore plays a key role in the immunoregulation of allergic responses and asthma [ 181 , 182 ]. Under physiological conditions, the major function of anti-inflammatory cytokines is to restrict the intensity and duration of pro-inflammatory responses and thereby prevent excessive immune-mediated bystander damage to host tissues [ 45 ].

Notably, IL-35, a more recently identified member of the IL-12 family composed of the Ebi3 and p35 subunits, has been recognized as a potent immunosuppressive cytokine. It is secreted mainly by Foxp3 + Treg [ 59 ]. Unlike classical IL-10, IL-35 exerts particularly strong inhibitory effects on T cells and can directly suppress proliferation of Th1 and Th17 cells. More uniquely, IL-35 can induce a novel subset of Treg, termed induced regulatory T 35 cell (iTr35) cells. Although these cells do not express Foxp3, they secrete large amounts of IL-35. This IL-35-driven paracrine suppressive loop plays a decisive braking role during remission of autoimmune diseases such as RA [ 59 ].

From a translational perspective, the physiological properties of these mediators provide potential therapeutic targets for inflammatory diseases, including direct supplementation with anti-inflammatory cytokines. However, compared with biologics such as neutralizing antibodies that directly block pro-inflammatory pathways, therapies based on direct administration of anti-inflammatory cytokines still face major limitations in pharmacokinetics and targeting specificity [ 183 ]. Conversely, under certain pathological conditions, excessive compensatory production of anti-inflammatory mediators may lead to profound immune suppression, thereby increasing the host’s susceptibility to fatal systemic infection [ 45 ]. For example, in late-stage sepsis and within the TME, Treg and their cytokines IL-10 and TGF-β are often pathologically overexpressed. This creates a potent suppressive microenvironment that directly inhibits the activation and cytotoxic function of effector T cells (such as CD8+ T cells needed for tumor clearance) and impairs B cell help, resulting in severe immune paralysis and a markedly reduced capacity of the host to clear pathogens or eliminate tumor cells [ 184 ] (Fig. 10 ).

It should also be noted that cytokines frequently exhibit marked pleiotropy and redundancy, such that a single cytokine may act on multiple target-cell types, while different cytokines may mediate similar biological effects [ 185 – 188 ]. Nevertheless, studies in gene-knockout animal models indicate that each cytokine still exerts distinct and nonredundant physiological functions because of differences in the spatiotemporal expression patterns and kinetics of their receptors in vivo. For example, although IL-1, IL-6, and TNF are all broadly classified as pro-inflammatory cytokines, the downstream pathways they activate and their tissue-specific effects are not identical across pathological contexts.

Through the preceding discussion of pro- and anti-inflammatory actions, it becomes clear that the ‘dual role’ of a cytokine is, at its core, a profound demonstration of context-dependency. Whether a given cytokine acts to fuel the inflammatory fire or to extinguish it is determined not by its intrinsic nature alone, but by the complex network in which it operates at a specific ‘time’ and in a specific ‘place’. For example, during the acute phase of an inflammatory response, IFN-γ may be a critical ‘warrior’ for pathogen clearance; however, its persistent expression during the resolution phase can transform it into a ‘culprit’ of chronic tissue damage.

This leads to a more sophisticated conclusion: our understanding of cytokines must shift from a static view of their ‘identity’ to a dynamic analysis of their ‘behavior’. This conceptual shift is not merely academic; it has direct and profound implications for clinical success and failure. It provides a fundamental explanation for why therapies targeting the same cytokine yield vastly different outcomes across different diseases, or even at different stages of the same disease—they intervene upon a dynamic actor playing disparate roles in different contexts. Future therapeutic strategies must therefore move beyond simple ‘blockade’ and learn how to ‘modulate,’ rather than ‘suppress,’ cytokine activity at the right time and in the right place. This represents the ultimate goal of personalized, precision immunomodulation.

The interplay between pro-inflammatory and anti-inflammatory cytokines is not a simple linear antagonism, but rather constitutes a highly complex and dynamic network that regulates immune homeostasis. This binary balance is achieved primarily through four core mechanisms.

First, there is a binary opposition between initiation and resolution. Pro-inflammatory cytokines such as IL-1β, IL-6, and TNF-α act as the “accelerators” of immune responses, initiating inflammation and activating immune cells at the onset of infection or tissue injury [ 189 ]. In contrast, anti-inflammatory cytokines such as IL-4, IL-10, and IL-13 act as “brakes” that counterbalance excessive pro-inflammatory signaling and promote inflammatory resolution [ 190 ].

Second, to prevent catastrophic immune overreactions, the immune system has evolved sophisticated negative-feedback loops. Elevation of pro-inflammatory signaling often triggers compensatory production of anti-inflammatory cytokines. For example, high expression of IL-1β and IL-6 promotes upregulation of IL-10, which in turn suppresses continued secretion of pro-inflammatory cytokines by immune cells and thereby limits excessive immune responses during infection [ 59 ].

Third, anti-inflammatory cytokines can directly inhibit pro-inflammatory signaling. In addition to indirect feedback regulation, IL-10 can significantly suppress transcription and expression of IL-1β and IL-6 in macrophages, monocytes, and T cells [ 191 , 192 ]. Similarly, IL-4 and IL-13 also exert strong anti-inflammatory effects by attenuating the ability of T cells and macrophages to secrete pro-inflammatory mediators [ 193 , 194 ].

Fourth, cytokines regulate polarization and differentiation of T-cell subsets. The cytokine profile of the microenvironment directly shapes the differentiation fate of naïve immune cells. A pro-inflammatory milieu dominated by IL-1β, IL-6, and TNF-α tends to promote development of pathogenic Th1 and Th17 subsets, thereby amplifying inflammation [ 195 , 196 ]. In contrast, an anti-inflammatory milieu dominated by IL-4 and IL-10 promotes differentiation of protective or regulatory T-cell populations. For example, IL-4 induces T helper 2 (Th2)-cell differentiation, and Th2 cells not only mediate antiparasitic immunity but also exert strong anti-inflammatory effects during tissue repair [ 197 , 198 ].

In summary, the dynamic interplay between pro-inflammatory and anti-inflammatory cytokines is not a zero-sum process of mutual cancellation, but a core mechanism by which the host finely regulates immune responses and maintains homeostasis. As research progresses, the complexity of this network crosstalk has become increasingly evident. Maintaining the delicate binary balance between these two arms is not only essential for appropriate immune defense, but also represents a fundamental safeguard against immune-mediated pathology.

Current status and challenges of targeted therapy

As a central hub regulating immune responses, the homeostatic balance of the cytokine network is essential for maintaining health, defending against pathogens, and eliminating tumor cells. In recent years, therapeutic strategies that directly target cytokines and their downstream signaling pathways have achieved major clinical advances in autoimmune diseases, severe inflammatory conditions, and cancer immunotherapy. For example, anti-TNF-α monoclonal antibodies such as infliximab [ 199 ], IL-6 receptor antagonists such as tocilizumab [ 199 ], and IL-17 inhibitors have become first-line treatments for diseases such as RA, IBD, and psoriasis [ 200 ]. In CS induced by severe infections such as COVID-19, IL-6 receptor antagonists and JAK inhibitors such as baricitinib have been shown to reduce mortality and improve outcomes in critically ill patients, although the optimal timing of intervention remains under debate [ 123 , 201 – 204 − 139 ] (Table 3 ). In the field of cancer immunotherapy, emerging technologies such as CAR-T-cell therapy [ 127 ], bispecific antibodies [ 44 ], and mRNA-based therapies are further advancing precision immunotherapy [ 57 , 226 ].

Nevertheless, the inherent complexity, pleiotropy, and redundancy of the cytokine network also pose major challenges to targeted intervention. These challenges are reflected primarily in heterogeneous efficacy, unpredictable off-target effects, secondary immunosuppression, and increased risk of opportunistic infection [ 227 – 231 ].

Clinical applications and efficacy

The “Double-edged sword”: context-dependent cytokine functions in the tumor Microenvironment

While cytokines are often categorized as ‘pro-inflammatory’ or ‘anti-inflammatory’, their functional roles within the TME are far from binary. Instead, their effects are highly context-dependent. The same cytokine can exert opposing functions—a classic ‘double-edged sword’—depending on its concentration, the target cell type, and the presence of other signals within the TME. This duality presents both significant challenges and unique opportunities for cytokine-targeted cancer therapies.

TGF-β is a prime example. In normal tissues and during early-stage tumorigenesis, it acts as a tumor suppressor by inhibiting cell proliferation and inducing apoptosis [ 232 ]. However, in advanced cancers, tumor cells often become resistant to its cytostatic effects and instead co-opt its signaling to promote tumor progression and immune evasion by inducing EMT, angiogenesis, and the differentiation of Tregs [ 233 – 236 ]. Similarly, TNF-α, the namesake ‘tumor necrosis factor’, can directly induce apoptosis in cancer cells but can also promote tumor survival and proliferation through chronic inflammation [ 237 ]. IL-6 is another quintessential example; it can support anti-tumor immunity by promoting T-cell activation, yet it can also drive tumor cell stemness and therapeutic resistance by activating the STAT3 pathway [ 238 – 240 ].

This context dependency is a major obstacle for current targeted therapies. For instance, systemic administration of a ‘pro-inflammatory’ cytokine like IL-2 or IFN-γ to stimulate anti-tumor immunity is often limited by severe systemic toxicities, such as CRS [ 241 , 242 ]. Conversely, global blockade of a ‘pro-tumor’ cytokine may interfere with its homeostatic functions in healthy tissues, leading to unintended autoimmune reactions [ 243 , 244 ].

However, this complexity also fuels innovation. The next generation of therapeutic strategies is moving beyond systemic ‘on/off’ approaches toward more precise and intelligent modulation. Key opportunities include: (1) Conditional Activation: Designing ‘pro-cytokines’ that are activated only under specific conditions of the TME (e.g., low pH or high protease activity) [ 245 , 246 ]. This enables localized, high-concentration delivery while minimizing systemic exposure and toxicity. (2) Targeted Delivery: Using antibody-cytokine fusion proteins (immunocytokines) or nanoparticle-based carriers to deliver cytokines specifically to tumor cells or defined immune cell subsets, achieving spatiotemporally precise immunomodulation [ 247 , 248 ]. (3) Combination Therapy: Integrating cytokine-based therapies with other modalities, such as ICIs. For example, local administration of IL-12 while blocking the PD-1/PD-L1 axis can more effectively activate T cells and remodel an immunosuppressive TME [ 249 ].

In summary, understanding and harnessing the ‘double-edged sword’ nature of cytokines is critical for developing the next generation of safer and more effective cancer immunotherapies.

Applications in autoimmune diseases

The pathological core of autoimmune diseases lies in breakdown of immune tolerance and pathological overexpression of pro-inflammatory cytokines. Targeted biologics developed against these mechanisms have achieved substantial therapeutic success.

Tumor necrosis factor-α (TNF-α) is a key cytokine in inflammatory responses and exists in both soluble (sTNF-α) and transmembrane (mTNF-α) forms, which bind to TNF receptor 1 (TNFR1) and TNF receptor 2 (TNFR2) to initiate intracellular signaling and mediate diverse immune and inflammatory processes [ 250 , 251 ]. The complexity of this ligand-receptor system endows drugs with different targeting strategies with distinct mechanisms of action and clinical profiles [ 250 , 252 ]. Anti-TNF-α therapy has achieved significant success in various autoimmune diseases, including rheumatoid arthritis (RA), inflammatory bowel disease (IBD), and psoriasis [ 250 , 253 , 254 ].

Six TNF-α inhibitors are currently approved for clinical use, which can be categorized by molecular structure into monoclonal antibodies (infliximab, adalimumab, golimumab, certolizumab pegol) and soluble receptor fusion proteins (etanercept) [ 250 , 255 ]. Both classes neutralize soluble TNF-α but exhibit marked differences in affinity for membrane-bound TNF-α. Monoclonal antibodies bind membrane-bound TNF-α with high efficiency，whereas etanercept, as a p75 TNF receptor-Fc fusion protein, has considerably lower affinity for this form of TNF-α [ 250 , 255 ]. This difference has clinical consequences.

Specifically, monoclonal antibodies such as infliximab and adalimumab not only neutralize sTNF-α [ 256 ], but also bind mTNF-α on the cell surface with high affinity [ 252 ]. This binding can induce apoptosis of mTNF-α-expressing cells through Fc receptor-mediated effector functions, such as antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) [ 257 ]. Concurrently, binding of monoclonal antibodies to mTNF-α blocks its interaction with TNFR-expressing effector cells and inhibits reverse signaling transmitted back into the mTNF-α-bearing cell [ 258 ]. In diseases dependent on cell-contact signals, such as IBD, this bidirectional blockade plays a critical role [ 259 ].

In contrast, etanercept acts primarily by binding sTNF-α to prevent its interaction with cell surface receptors [ 260 ]. However, its binding efficiency for mTNF-α is substantially lower than that of monoclonal antibodies [ 255 ]. This difference has significant clinical implications, particularly in the treatment of IBD. Intestinal inflammation in IBD, especially Crohn’s disease, relies heavily on mTNF-α-mediated cell-contact signals and reverse signaling [ 261 ]. Because of its low affinity for mTNF-α, etanercept failed to show superiority over placebo in randomized controlled trials for Crohn’s disease [ 262 ]. Moreover, multiple case reports have documented new-onset IBD or exacerbation of pre-existing IBD during etanercept therapy [ 263 , 264 ], such paradoxical reactions are considered to result from the inability of etanercept to effectively neutralize mTNF-α [ 257 ]. Weak binding to mTNF-α cannot adequately block TNF-TNFR pro-inflammatory signaling, tipping the intestinal immune homeostasis toward a pro-inflammatory state. In contrast, monoclonal anti-TNF antibodies effectively induce and maintain remission in IBD [ 257 , 265 , 266 ]. This mechanistic distinction explains why etanercept is ineffective in treating IBD, whereas monoclonal anti-TNF antibodies are first-line biologics. Thus, even when targeting the same cytokine, differences in mechanism of action can lead to divergent clinical outcomes in different disease contexts, underscoring the importance of cytokine network complexity in translational medicine [ 267 ]. When selecting therapeutic strategies, the distinct forms of the target molecule and their downstream biological effects must be taken into account.

IL inhibitors: Ustekinumab targets the p40 subunit shared by IL-12 and IL-23, thereby blocking Th1- and Th17-cell differentiation at an upstream level, and has shown strong efficacy in moderate-to-severe IBD, with clinical remission rates of approximately 40–50% [ 201 , 268 ]. Tocilizumab, an IL-6 receptor antagonist, has significant efficacy in RA patients with inadequate response to conventional synthetic disease-modifying antirheumatic drugs, rapidly relieving joint symptoms while also slowing radiographic progression of bone destruction [ 199 ]. In addition, IL-17 inhibitors such as secukinumab have substantially reshaped treatment of psoriasis and ankylosing spondylitis [ 200 , 269 ].

The mechanistic differences among TNF inhibitors are not an isolated phenomenon. In therapeutic strategies targeting the IL-6 pathway, the structure-function relationship also carries clinical significance [ 270 ]. Current strategies targeting the IL-6 pathway can be divided into two categories: direct neutralization of the IL-6 ligand (e.g., siltuximab) and blockade of the IL-6 receptor (e.g., tocilizumab, sarilumab) [ 270 ]. Clinical observations indicate that merely neutralizing circulating IL-6 ligand is often insufficient to achieve full efficacy, because locally formed complexes of IL-6 with soluble IL-6 receptor can still activate cells broadly expressing gp130 through trans-signaling [ 271 ]. Based on this understanding, tocilizumab (a monoclonal antibody blocking the IL-6 receptor α-chain) has achieved success in multiple diseases. Tocilizumab simultaneously blocks classical cis-signaling and trans-signaling, effectively curbing IL-6-driven inflammation [ 272 ]. However, blocking the IL-6 receptor also ablates reverse signaling mediated by membrane-bound IL-6 R. Under physiological conditions, when IL-6 binds to the membrane-bound receptor, it not only activates classical forward signaling but also allows the intracellular domain of the receptor to transmit signals back into its own cell (i.e., reverse signaling), participating in the regulation of cell activation and survival [ 270 ]. Complete blockade of this signaling may be related to certain adverse events observed during long-term anti-IL-6 R therapy, such as a slightly increased risk of intestinal perforation. Therefore, selectively preserving reverse signaling or developing novel agents that exclusively block trans-signaling (e.g., sgp130Fc fusion protein) represents an important direction in this field [ 271 ]. Notably, reverse signaling in the TNF system is mediated by the membrane-bound ligand mTNF-α—that is, signals are transmitted from the receptor to the ligand-expressing cell—whereas reverse signaling in the IL-6 system is mediated by the membrane-bound receptor mIL-6 R, with the intracellular domain activating its own cell. Although both are referred to as reverse signaling, the direction of signal flow differs: intervention in TNF system reverse signaling requires blocking the ligand, whereas intervention in the IL-6 system requires blocking the receptor. Consequently, the optimized targeting strategies for these two systems cannot be generalized.

Post-receptor signal blockade and JAK inhibitors: In addition to extracellular neutralization of cytokines, inhibition of intracellular post-receptor signaling cascades has become another key therapeutic strategy. Small-molecule JAK inhibitors such as tofacitinib and baricitinib block JAKs and thereby simultaneously inhibit signaling by multiple cytokines, including IL-2, IL-6, and IFN-γ, through the JAK-STAT pathway. Compared with biologics, oral JAK inhibitors offer more convenient administration and rapid onset of action, but their use requires close monitoring for risks such as herpes zoster reactivation and venous thromboembolism (VTE).

Type I IFN inhibition: Given the prevalent IFN signature in systemic lupus erythematosus, monoclonal antibodies targeting the type I IFN receptor, such as anifrolumab, have now been approved, filling a long-standing therapeutic gap in systemic lupus erythematosus.

Applications in severe inflammatory states

In critical illness caused by severe infection, uncontrolled immune activation can trigger destructive CS characterized by explosive release of pro-inflammatory cytokines such as IL-6, IL-1β, TNF-α, and IFN-γ, leading to ARDS, systemic vascular leakage, disseminated intravascular coagulation, and MODS. Targeted cytokine therapy is therefore crucial in this setting, although its efficacy depends strongly on disease stage, timing of administration, and patient stratification.

IL-6 receptor antagonists: A large meta-analysis involving more than 10,000 critically ill patients showed that tocilizumab significantly reduced 28-day mortality in severe COVID-19, with an approximate relative risk reduction of 12% (RR 0.88, 95% CI 0.82–0.95) [ 123 ]. However, this benefit is highly time-dependent: the greatest survival benefit is observed when treatment is given during the inflammatory window of opportunity, typically within 72 hours of admission, when inflammatory markers such as C-reactive protein and IL-6 are sharply elevated but before invasive mechanical ventilation is required. Once the disease progresses to late-stage irreversible tissue injury, the therapeutic effect is substantially reduced [ 204 , 273 ]. This underscores the importance of timely intervention, which maximizes benefit while minimizing prolonged systemic immunosuppression. In CAR-T-cell therapy, where 70–90% of patients may develop CRS, tocilizumab is the standard first-line treatment and can rapidly reverse life-threatening manifestations such as high fever and hypotension without compromising the antitumor activity of CAR-T cells [ 123 ].

JAK inhibitors: As broad intracellular signaling inhibitors, JAK inhibitors such as baricitinib suppress signal amplification by multiple cytokines, including IL-6, IL-2, IFN-γ, IL-12, IL-23, and members of the IFN family, by targeting the JAK-STAT pathway. In COVID-19, several meta-analyses have shown that JAK inhibitors reduce 28-day mortality in severe disease by approximately 15% and significantly reduce the need for mechanical ventilation by about 20–25% [ 126 , 274 ]. Importantly, in patients with severe infection or autoimmune CS who do not respond adequately to single-target TNF-α or IL-6 inhibition, JAK inhibitors may serve as effective salvage therapy because they can overcome compensatory redundancy within the cytokine network [ 201 ].

IL-1β blockade: Anakinra, a recombinant IL-1 receptor antagonist, blocks IL-1β-driven inflammatory toxicity by competitively binding the receptor. In patients with sepsis-associated hyperinflammatory phenotypes, such as a C-reactive protein level > 150 mg/L or a ferritin level > 500 μg/L, anakinra may reduce 28-day mortality by approximately 10–15% without increasing the risk of secondary infection. Its main mechanism is effective suppression of IL-1β-driven neutrophil overrecruitment and endothelial barrier disruption. In systemic juvenile idiopathic arthritis complicated by macrophage activation syndrome, as well as in adult-onset Still’s disease, anakinra is also a first-line life-saving therapy for the rapid reversal of hyperpyrexia, severe cytopenias, and coagulopathy.

Applications in tumor therapy

Beyond a systematic summary of established cytokine biology and clinical applications of key cytokine-targeting agents, we leverage this foundational knowledge to pose a forward-looking, field-defining question: Where does the immunomodulation field go from here? We argue that, after decades of clinical success with broad-acting agents, the future of therapy lies in a granular understanding of pathway-specific pathology and the development of predictive tools. This review concludes by synthesizing these themes into a perspective on the key challenges and transformative opportunities shaping the next era of inflammatory disease treatment.

Cytokines play a highly paradoxical dual role in the TME. On the one hand, pro-inflammatory signals such as IL-2 and IFN-γ, together with Th1-skewed responses, can strongly enhance the cytotoxic activity of CTLs and NK cells [ 275 ]. On the other hand, immunosuppressive cytokines such as TGF-β, IL-10, and IL-6 continuously recruit Treg and MDSCs, thereby promoting tumor immune evasion and angiogenesis [ 276 , 277 ]. Ideally, cytokine-based antitumor therapy must therefore achieve a highly precise balance between activating effector immunity and avoiding tumor-promoting or immunosuppressive effects.

IL-2: High-dose IL-2 was approved by the Food and Drug Administration (FDA) for treatment of advanced renal cell carcinoma and melanoma because of its potent ability to expand CD8 + T cells and NK cells, and a subset of patients achieved long-term clinical remission lasting more than a decade [ 278 , 279 ]. However, wild-type IL-2 also binds the high-affinity receptor CD25 expressed on Treg cells, thereby paradoxically enhancing immunosuppression [ 280 , 281 ]. This limitation has driven development of selective IL-2 agonists. For example, bempegaldesleukin uses PEGylation-based steric hindrance to preferentially activate CD8 + T cells and NK cells while minimizing stimulation of Treg cells [ 282 ]. Such engineered variants can broaden the therapeutic window and show promise in combination therapy for advanced solid tumors [ 283 ].

IL-15: IL-15 shares the IL-2 Rβγ signaling pathway with IL-2 but does not rely on CD25, thereby mechanistically avoiding pathological Treg activation [ 284 ]. Recombinant IL-15 and long-acting superagonists such as ALT-803 have shown strong ability to expand NK cells and memory T cells in relapsed or refractory hematologic malignancies and solid tumors [ 285 , 286 ]. Early clinical evidence suggests that IL-15 combined with PD-1 blockade can help reverse profound immunosuppression within the TME and restore antitumor immunity in patients resistant to monotherapy [ 287 , 288 ]. Furthermore, engineering CAR-T cells to express IL-15 can markedly improve their persistence and cytotoxic durability within hostile solid-TMEs [ 289 ].

IL-27: As a member of the IL-12 family, IL-27 exhibits distinctive multidimensional antitumor activity. It can directly induce tumor-cell apoptosis and inhibit angiogenesis by downregulating VEGF through activation of STAT1/3 signaling [ 290 ], while also promoting cytotoxic T lymphocyte (CTL) differentiation and suppressing the immunosuppressive functions of Th17 and Treg cells [ 291 ]. Fusion proteins and gene-delivery platforms based on IL-27 are currently under active development.

TNF-α: TNF-α shows striking dose-dependent behavior in oncology. Very high local concentrations of TNF-α, such as those achieved by isolated limb perfusion, can directly induce acute apoptosis of tumor vascular endothelial cells and cut off tumor blood supply [ 292 ]; this approach has been used successfully for limb-sparing treatment of unresectable soft tissue sarcoma. In contrast, prolonged exposure to low-dose TNF-α can chronically activate NF-κB signaling, thereby promoting protumor inflammation, angiogenesis, and metastasis [ 293 ].

TGF-β inhibitors: TGF-β is widely regarded as one of the most potent immunosuppressive cytokines in the TME. It suppresses CTL and NK-cell function, induces Treg differentiation, and directly promotes epithelial-mesenchymal transition in tumor cells. Accordingly, agents such as bintrafusp alfa, a bifunctional fusion protein targeting both TGF-β and PD-L1, and high-affinity TGF-β traps such as Avid200 have been developed [ 294 ]. These agents have shown encouraging early clinical signals in non-small cell lung cancer and biliary tract cancer, particularly with respect to reversing stromal fibrosis and overcoming immune tolerance [ 295 , 296 ].

Beyond the aforementioned indications, cytokine-targeted therapy has also established an evidence-based position in several specific diseases. In polymyalgia rheumatica, IL-6 receptor antagonists are recommended as an alternative or steroid-sparing regimen for glucocorticoid-dependent or intolerant patients [ 270 ]. Sarilumab has received FDA approval for patients with inadequate response to glucocorticoids or inability to taper [ 297 ]，and tocilizumab has also shown potential to replace glucocorticoids in some studies [ 270 ]. In crystal arthropathies, IL-1 pathway-targeted therapy has been applied: canakinumab (anti-IL-1β monoclonal antibody) is approved for acute attacks of refractory gout and pseudogout [ 298 ], and anakinra (recombinant IL-1 receptor antagonist) can serve as an alternative when glucocorticoids are contraindicated, with efficacy and safety confirmed by clinical studies [ 298 ]. In hidradenitis suppurativa, a chronic inflammatory skin disease, IL-1β plays a key role in follicular occlusion and inflammatory cascade amplification; a randomized controlled trial showed that anakinra achieved favorable efficacy in severe hidradenitis suppurativa, significantly improving clinical response and providing a new therapeutic option for this refractory disease [ 269 ]. Additionally, in oncology, TNF-α has demonstrated unique therapeutic potential. Administered at ultra-high local concentrations via isolated limb perfusion, TNF-α directly induces apoptosis of tumor vascular endothelium and ablates the tumor blood supply, becoming an integral component of limb-sparing treatment for unresectable soft tissue sarcomas [ 250 , 253 ]. For instance, in ILP treatment for locally advanced extremity soft tissue sarcomas and melanomas, the combination of TNF-α with chemotherapeutic agents (e.g., melphalan) significantly improves the objective response rate, achieving a complete response rate of up to 70% in regional metastatic melanoma of the limbs [ 250 ]. The European Society for Medical Oncology (ESMO) guidelines explicitly recommend ILP with TNF-α and melphalan for selected patients with locally advanced extremity soft tissue sarcomas, especially those with unresectable or recurrent disease, to improve limb salvage rates and local control [ 250 ]. The diametrically opposite effects of this cytokine in different disease contexts represent a vivid illustration of the dualistic balance of the cytokine network in clinical medicine [ 254 ]. These expanded indications demonstrate that intervention in the cytokine network requires integrated consideration of the target, disease context, and route of administration—this context-based precision modulation is precisely the core direction for the evolution of future cytokine-targeted therapies from “broad-spectrum blockade” to “precision intervention.”

Emerging therapies and technological frontiers

To overcome the limitations of traditional single-molecule targeted therapies in specificity and systemic toxicity, a series of technological innovations is rapidly reshaping strategies for intervention in the cytokine network.

Bispecific antibodies

Bispecific antibodies, including bispecific T-cell engagers, function through a physical bridging mechanism: one arm binds a tumor-associated antigen, whereas the other binds CD3 on T cells, thereby redirecting circulating immune cells into the TME for close-range cytotoxic activity. For example, Tarlatamab is a DLL3-targeted bispecific antibody that links DLL3-positive small-cell lung cancer cells to CD3-positive T cells [ 44 ]. This not only potently activates local T-cell function, but also remodels the TME through release of effector cytokines. Such an architecture markedly improves targeting specificity and reduces the risk of broad systemic immune activation associated with conventional systemic therapy.

Chimeric antigen receptor cell therapies and expansions

Using advanced gene-editing technologies such as clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9), modern CAR-T cells can be endowed with armored properties. Through engineered genetic circuits, these cells are able to secrete prosurvival cytokines such as IL-15 and IL-23 autonomously and locally after recognizing tumor antigens [ 44 , 52 , 128 ]. For example, membrane-tethered IL-12 expressed on CAR-T cells can generate highly concentrated antitumor immune stimulation locally within tumors while avoiding the severe systemic toxicity associated with intravenous administration of free IL-12 [ 128 , 129 ].

To overcome immune escape caused by tumor downregulation of MHC class I molecules, non-T-cell-based CAR therapies have opened new avenues for cytokine-mediated modulation. CAR NK cell (CAR-NK) cells possess broad non-MHC-restricted cytotoxicity, and their engineered secretion of IFN-γ and TNF-α can induce tumor cells to re-express MHC and ICAM-1, thereby improving recognition and infiltration by endogenous T cells. CAR-macrophage therapy is distinctive in its ability to reprogram the local immune milieu. Through genetic engineering, CAR-macrophage cells can be stably maintained in a pro-inflammatory M1-like state. After infiltrating tumors, they secrete large amounts of TNF-α, IL-1β, and IL-12, thereby antagonizing the M2-dominant protumor network within the TME. This local repolarization effect may be crucial for converting immunologically cold tumors into hot tumors that are responsive to immune attack [ 52 , 57 , 127 , 226 , 299 , 300 ].

mRNA-based therapeutic technologies

The mRNA-lipid nanoparticle platform, which proved highly effective during the COVID-19 pandemic, is now being rapidly extended into immune regulation because of its flexibility and rapid development cycle.

Personalized tumor vaccines: Personalized vaccines exemplified by mRNA-4157 encode patient-specific tumor neoantigens, while the lipid nanoparticle carrier and RNA backbone themselves possess intrinsic adjuvant activity. After administration, these formulations activate TLRs and the retinoic acid-inducible gene I pathway, inducing a local cytokine response centered on type I IFNs in draining lymph nodes. This in situ pro-inflammatory microenvironment is critical for promoting full dendritic-cell maturation, efficient antigen cross-presentation, and robust systemic T-cell responses [ 57 ].

In vivo synthesis of antibodies and cytokines: Through rational sequence design, mRNA technology can transform host tissues into in vivo bioreactors capable of producing monoclonal antibodies or short-lived therapeutic cytokines locally and on demand, including molecules that are otherwise difficult to manufacture ex vivo. This in situ synthesis strategy enables highly precise local delivery and may fundamentally reduce the systemic toxicity associated with high-dose cytokine therapy [ 57 , 226 ].

Potential risks and side effects of targeting the cytokine network

Because the cytokine network is highly complex and globally interconnected, therapeutic intervention inevitably entails substantial risk. A deep understanding of these risks, together with prospective toxicity management, is essential for the safe application of cytokine-targeted therapies.

Immunosuppression and infection risks

Most biologics targeting pro-inflammatory pathways such as TNF or IL-6 ultimately act by attenuating immune function. This nonphysiological blockade significantly increases susceptibility to bacterial, viral, and fungal infection. For example, prolonged TNF-α inhibition compromises granuloma integrity and markedly increases the risk of reactivating latent intracellular pathogens such as Mycobacterium tuberculosis; accordingly, screening for latent tuberculosis has become a mandatory pretreatment measure [ 227 ]. Similarly, broad immunosuppression induced by high-dose glucocorticoids is strongly associated with increased opportunistic infection and mortality in patients with COVID-19 [ 227 , 228 , 230 , 231 ]. Therefore, longitudinal microbiological monitoring and proactive anti-infective prophylaxis are prerequisites for implementing these treatment strategies.

Cytokine release syndrome

CRS is the most severe acute life-threatening toxicity associated with potent immune-activating therapies such as CAR-T cells and bispecific antibodies. Its pathological basis lies in abrupt and excessive activation of immune cells, especially T cells and monocyte/macrophage lineage cells, which rapidly release large quantities of IFN-γ, IL-6, TNF-α, and other pro-inflammatory mediators into the circulation [ 127 , 129 , 230 ]. Clinically, patients may deteriorate rapidly from early flu-like fever to refractory hypotension, capillary leak syndrome, and even multiple organ failure. A large body of evidence indicates that IL-6 is the central hub driving the CRS inflammatory network [ 301 ]. Accordingly, pre-emptive or early tocilizumab administration to block IL-6 R has become the international standard for management of moderate-to-severe CRS. Current efforts to establish early-warning models based on baseline tumor burden and early IL-6 kinetics are crucial for reducing CRS-related mortality [ 129 , 301 ].

Off-target effects and paradoxical immune imbalance

Because cytokines are highly pleiotropic, blockade of a single molecule often leads to broader network effects. Disruption of a key node such as IFN-γ or TGF-β inevitably interferes with its physiological roles in maintaining tissue homeostasis and may therefore cause unexpected off-target injury [ 228 ]. An especially challenging issue is the occurrence of paradoxical reactions. Some patients with autoimmune disease treated with anti-TNF-α or anti-IL-17 agents not only fail to improve, but also develop de novo psoriasis-like eruptions or IBD [ 228 ]. These counterintuitive phenomena are thought to arise from structural remodeling and compensatory bypass activation within the cytokine network following strong therapeutic perturbation. In addition, immune homeostasis depends on precise endogenous negative-feedback systems such as SOCS-family proteins. Artificial intervention may bypass or disrupt these natural regulatory brakes, causing the balance to shift in the opposite direction and even precipitating new autoimmune syndromes [ 228 , 230 ]. These observations highlight the need for future strategies to move from blunt blockade toward fine-tuned modulation of the cytokine network.

Efficacy heterogeneity and precision medicine challenges

Despite major clinical successes, response to cytokine-targeted therapy shows considerable interindividual heterogeneity. Differences in genetic background, immune phenotype, tissue microenvironment, and even the gut microbiome may all produce markedly different responses to the same drug [ 126 , 201 ]. Clinically, up to 30–40% of patients with RA show primary nonresponse to their first TNF-α inhibitor, resulting in prolonged therapeutic trial and error [ 199 ].

This challenge underscores the importance of precision medicine based on biomarkers and molecular stratification [ 126 , 268 ]. For example, baseline serum IL-6/C-reactive protein kinetics and single-nucleotide polymorphisms in the TNF-α promoter may help predict sensitivity to specific biologics [ 199 ]. More broadly, integrative multi-omics approaches combining genomics, transcriptomics, and metabolomics may identify higher-dimensional predictive signatures and enable tailored therapies for patients with refractory disease, thereby maximizing efficacy while minimizing toxicity [ 301 ].

Future perspectives and research directions

Precision targeting of the cytokine network has become a central strategy for treating autoimmune diseases, controlling severe inflammatory storms, and overcoming tumor immune tolerance. From monoclonal antibodies to engineered living-cell therapies such as CAR-based platforms, and further to in vivo mRNA synthesis systems, therapeutic modalities are rapidly evolving toward greater personalization and intelligence [ 44 , 127 , 129 , 226 ].

Nevertheless, the redundancy, pleiotropy, and dynamic behavior of the cytokine network remain major barriers to definitive therapeutic success. Long-term systemic immune suppression carries risks of infection and secondary malignancy; excessive immune activation may induce fatal CRS; and network remodeling may cause paradoxical immune imbalance [ 129 , 228 , 230 , 231 ].

The therapeutic landscape for inflammatory diseases is at a crossroads. Having established the power of cytokine blockade, the next chapter of innovation will be defined not by broader strokes, but by greater precision. Several key areas are critical for this evolution. Perhaps the most pressing need is the development of robust predictive biomarkers. The current ‘trial-and-error’ approach to prescribing these powerful and costly agents is unsustainable. The ability to match the right patient to the right drug at the outset, informed by their unique molecular or cellular signature, remains the central, yet unrealized, promise of personalized medicine in this field.

First, precision immunomodulation should be a primary goal. Systems immunology is needed to clarify the dynamic compensatory behavior of cytokine networks and the mechanisms by which negative-feedback regulators such as SOCS fail in different pathological microenvironments [ 126 ]. Combined with high-throughput multi-omics approaches, this knowledge may enable identification of predictive biomarker panels and generation of individualized immune intervention maps, thereby shifting treatment from blind blockade of single signals to rational restoration of network homeostasis [ 228 – 230 ].

At the same time, the therapeutic pipeline is rightly evolving beyond conventional monoclonal antibodies. New strategies, such as bispecific antibodies, small molecule inhibitors targeting intracellular signaling, and even engineered cell therapies, are not just incremental improvements. They represent a conceptual shift toward modulating pathways with greater finesse—targeting multiple nodes at once or intervening further downstream to potentially limit off-target effects and overcome resistance mechanisms. Optimization of therapeutic strategies and technological innovation are essential for improving efficacy. In diseases with highly resilient pathological microenvironments, such as solid tumors, the limitations of single-target therapy must be overcome [ 57 , 226 ]. Combination approaches integrating cytokine engineering with immune checkpoint blockade, metabolic reprogramming, or conventional radiochemotherapy may provide synergistic benefit. In parallel, advances in nanotechnology and targeted mRNA-lipid nanoparticle delivery systems may enable development of smart platforms responsive to microenvironmental changes, allowing toxic cytokines to be released locally, on demand, and at controlled doses, thus expanding the therapeutic window [ 57 , 226 ].

Third, comprehensive toxicity management is indispensable for safe clinical translation. High efficacy must be accompanied by rigorous safety control. For acute CRS and neurotoxicity induced by living-cell therapies such as CAR-T cells, there is an urgent need for real-time early-warning models based on early molecular features, together with standardized intervention protocols. In addition, next-generation therapies incorporating suicide switches or graded activation logic may provide clinicians with an emergency mechanism for terminating uncontrolled immune activation. Only within a framework of controllable risk can the full therapeutic potential of cytokine network targeting be realized and translated into meaningful patient benefit [ 129 ].

Ultimately, these research directions are not independent pursuits; they are deeply interconnected. A biomarker might reveal a resistance mechanism that a next-generation therapy is specifically designed to overcome. The goal, therefore, is to move from broadly suppressing inflammation to precisely re-calibrating the specific immune dysregulation driving each patient’s disease.

Conclusion

The cytokine network is a core mechanism underlying immune homeostasis, and its physiological function depends on the dynamic balance between pro-inflammatory and anti-inflammatory signaling. This review has systematically summarized the compositional features of the cytokine network and its dual roles in physiological and pathological settings. Although targeted therapies represented by monoclonal antibodies and JAK inhibitors have transformed the treatment landscape of autoimmune disease and cancer, clinical experience indicates that blockade of a single cytokine or signaling pathway alone often fails to achieve durable and broadly effective outcomes. A major reason for this limitation lies in three inherent properties of the cytokine network: pleiotropy, redundancy, and heterogeneity. A major reason for this limitation lies in the inherent properties of the cytokine network: pleiotropy, redundancy, and heterogeneity, as well as the context-dependent ‘double-edged sword’ effects that are particularly prominent in complex pathologies like cancer. Future breakthroughs will likely depend not on simply blocking or activating single pathways, but on developing intelligent strategies capable of spatiotemporally precise modulation to favorably tip this balance.

First, the cytokine network exhibits substantial functional redundancy. Blockade of a single pathway may activate compensatory circuits, thereby leading to therapeutic resistance or recurrence of inflammation. For example, after inhibition of IL-6 signaling, other cytokines with overlapping functions, such as leukemia inhibitory factor and oncostatin M, may continue to sustain inflammation. Second, cytokine pleiotropy means that the same cytokine may exert vastly different, even opposing, effects across tissues or disease stages. For instance, TGF-β suppresses tumor growth in early stages but promotes metastasis in later stages. This complexity means that systemic administration can easily cause off-target effects or unintended immunosuppression, thereby increasing the risk of infection and tumorigenesis. Third, interindividual heterogeneity is also a major determinant of therapeutic response, as differences in baseline immune status strongly influence sensitivity to specific targeted agents.

Accordingly, immunotherapy is now undergoing a paradigm shift from broad blockade toward precise regulation. This transition is reflected at three levels. First, therapeutic targets are becoming more precise. Approaches such as bispecific antibodies and engineered cell therapies, including CAR-T cells, allow selective intervention in specific cell subsets or local lesions, thereby reducing systemic toxicity. Second, patient stratification is becoming more refined. Predictive biomarkers identified through multi-omics approaches, such as particular genetic polymorphisms or cytokine signatures, can be used to identify patients most likely to benefit before treatment begins, thereby avoiding ineffective therapy. Third, regulatory strategies are becoming more dynamic. Rather than simply suppressing inflammation, future approaches should seek to restore endogenous balance within the immune network. Smart delivery systems and synthetic biology technologies may enable real-time adjustment of drug release according to inflammatory activity in vivo, allowing dynamic correction of aberrant immune responses.

Ultimately, the physiological and pathological functions of the cytokine network are determined by the binary balance between pro-inflammatory and anti-inflammatory signals. Under physiological homeostasis, this dynamic balance supports appropriate immune activation for pathogen clearance and tissue repair. Under pathological conditions, however, disruption of this balance leads to uncontrolled immune responses that may culminate in CRS or CS, causing multi-organ injury. Therefore, the future of immunotherapy does not lie in finding more sledgehammers to block entire pathways. Rather, it depends on a sophisticated understanding of cytokine duality. The insights are not just academic; they form the very blueprint for developing next-generation therapeutics that can selectively inhibit pathogenic actions while preserving homeostatic functions. That is the field’s next great challenge and its most promising frontier.

Acknowledgements

None.

Abbreviations

protein kinase B

AMP-activated protein kinase

acute respiratory distress syndrome

bispecific T-cell engager

Cancer-associated fibroblast

Chimeric antigen receptor

chimeric antigen receptor natural killer cell

chimeric antigen receptor T cell

CRISPR-associated protein 9

C-C motif chemokine ligand 2

cyclic GMP-AMP synthase

coronavirus disease 2019

clustered regularly interspaced short palindromic repeats

C-reactive protein

cytokine release syndrome

cytokine storm

colony-stimulating factor

cytotoxic T lymphocyte

cytotoxic T-lymphocyte-associated protein 4

C-X3-C motif chemokine ligand 1

C-X-C motif chemokine ligand

C-X-C motif chemokine ligand 8

damage-associated molecular patterns

dendritic cell

extracellular matrix

epidermal growth factor

extracellular signal-regulated kinase

Food and Drug Administration

forkhead box P3

granulocyte colony-stimulating factor

granulocyte-macrophage colony-stimulating factor

glycoprotein 130

hypoxia-inducible factor 1-alpha

high-mobility group box 1

inflammatory bowel disease

intercellular adhesion molecule 1

interferon

interferon-alpha

interferon-beta

interferon-gamma

insulin-like growth factor

interleukin

interleukin-18-binding protein

interleukin-1 receptor antagonist

interleukin-1 receptor-associated kinase

insulin receptor substrate 1

induced regulatory T cells 35

Janus kinase

lipopolysaccharide

lymphotoxin-alpha

macrophage colony-stimulating factor

mitogen-activated protein kinase

monocyte chemoattractant protein 1

myeloid-derived suppressor cells

major histocompatibility complex

mixed lineage kinase domain-like protein

matrix metalloproteinase

multiple organ dysfunction syndrome

mitochondrial DNA

mechanistic target of rapamycin

mechanistic target of rapamycin complex 1

Myeloid differentiation primary response 88

Neutrophil extracellular traps

Nuclear factor kappa-light-chain-enhancer of activated B cells

Natural killer

NOD-like receptor protein 3

Pathogen-associated molecular patterns

Programmed cell death protein 1

Programmed death-ligand 1

Phosphoinositide 3-kinase

Rheumatoid arthritis

Receptor activator of nuclear factor kappa-B ligand

Receptor-interacting protein kinase

Retinoic acid receptor-related orphan receptor gamma t

Reactive oxygen species

Src homology region 2 domain-containing phosphatase 1

Suppressor of cytokine signaling

Signal transducer and activator of transcription

Stimulator of interferon genes

TAK1-binding protein 2

Transforming growth factor-beta-activated kinase 1

Transforming growth factor-beta

T helper

T helper 1

T helper 17

T helper 2

Toll-like receptor

Tumor microenvironment

Tumor necrosis factor

Tumor necrosis factor-alpha

Tumor necrosis factor-beta

Tumor necrosis factor receptor 1

Tumor necrosis factor receptor 2

TNF receptor-associated factor

Regulatory T cells

TIR-domain-containing adapter-inducing interferon-β

Tissue-resident memory T cells

Vascular cell adhesion molecule 1

Vascular endothelial growth factor

Venous thromboembolism

Author contributions

Yixiao Zhang, Dezhi Guo, Yuanhang Zhou and Changli Wang contributed to the manuscript writing and figure preparation, Guowei Su, Jie Huang and Yiwen Wan designed the work, Haoling Zhang, Haifang Wan, Lulong Bo and Wangzheqi Zhang supervised the work. All authors have read and approved the article. All authors read and approved the final manuscript.

Funding

This study was funded The National Natural Science Foundation of China (82302421).

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethical approval

Not applicable.

Human and animal rights

Not applicable. This manuscript does not contain any studies with human participants or animals performed by any of the authors.

Consent for publication

Not applicable. This manuscript does not include details, images, or videos relating to an individual person.

Competing interests

The authors declare no competing interests.

Footnotes

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Yixiao Zhang, Dezhi Guo, Yuanhang Zhou and Changli Wang contributed equally to this work.

Contributor Information

Haoling Zhang, Email: zhanghaolingedu@163.com.

Haifang Wan, Email: yb2218204@zju.edu.cn.

Lulong Bo, Email: bartbo@smmu.edu.cn.

Wangzheqi Zhang, Email: zwzq001031@smmu.edu.cn.

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Associated Data

Data Availability Statement

No datasets were generated or analysed during the current study.