CD4 T helper cells (Th) are pivotal in adaptive immunity. Subtypes include Th1, Th2, Th17, Tfh, and regulatory T cells (Treg), defined by their cytokine profiles (11). Th2 cells mediate adaptive responses to parasites, allergens (e.g., dust mites, molds), and helminths (12). Allergen-stimulated epithelial cells release IL-25, IL-33, and thymic stromal lymphopoietin (TSLP), activating ILC2s to amplify allergic inflammation (13).

Th2-derived cytokines (IL-4, IL-5, IL-13) regulate parasitic infections, immune regulation, and multisystem homeostasis (14). These cytokines are extensively involved in the pathogenesis of allergic inflammatory diseases, including asthma, allergic rhinitis (AR), atopic dermatitis, and chronic rhinosinusitis. IL-4 and IL-13 induce B cells to promote the production of IgE and selectively activate macrophages (15, 16). IL-13 directly acts on epithelial cells and smooth muscle cells, driving mucus secretion, airway remodeling, and airway hyperresponsiveness, while IL-5 enhances eosinophil maturation, migration, and function (17, 18). Thus, IL-4, IL-5, and IL-13 are the primary effector cytokines produced by Th2 cells during type 2 immune responses. Notably, the genes encoding these three cytokines are clustered within a single genomic segment and are regulated by the locus control region (LCR) of the Rad50 gene (19).

In recent years, in addition to adaptive immune cells, certain innate lymphoid-like cells have been recognized to play critical roles in immunity and inflammation, particularly in early immune responses to helminth infections, allergen-induced airway inflammation, and tissue repair. ILC2s are members of the innate immune system that do not rely on antigen-specific receptors [T cell receptor(TCR)/B cell receptor (BCR)] and according to transcription factors and functions, they can be classified into three subsets: ILC1s (combat viral/intracellular pathogens; dependent on T-bet; secrete IFN-γ), ILC2s (respond to parasites/allergic reactions; dependent on GATA3/RORα; secrete IL-5, IL-13, and IL-9), and ILC3s (target extracellular bacteria/mucosal homeostasis; dependent on RORγt; secrete IL-17 and IL-22) (20, 21).

ILC2s predominantly express surface markers such as CD127 (IL-7Rα), CRTH2 (CD294), CD161, and ST2 (IL-33R) (12). They originate from common lymphoid progenitors (CLPs) in the bone marrow and further differentiate in tissues such as the thymus, gut, and lungs (12). The transcription factors GATA3, RORα, and Id2 are key regulators of ILC2 development and function (22, 23). As central effector cells in type 2 immunity, ILC2s are activated via the IL-33/ST2 and IL-25/IL-17RB signaling pathways. Upon activation, they rapidly release large quantities of type 2 cytokines to amplify type 2 inflammatory responses. Although their functions partially overlap with those of Th2 cells, ILC2s lack antigen specificity (24). Due to their rapid responsiveness and widespread presence in healthy tissues, ILC2s also play essential roles in maintaining physiological homeostasis (25).

The pathogenesis of CRSwNP is closely linked to type 2 immune responses. ILC2s play a critical role in the formation of nasal polyps in patients with type 2 chronic rhinosinusitis. Recent studies highlight that the synergistic interaction between Th2 cells and ILC2s in driving local inflammation, tissue remodeling, and disease recalcitrance constitutes a core mechanism underlying CRSwNP progression (Figure 1). Research has demonstrated the presence of ILC2s in sinonasal mucosa, particularly in nasal polyps, where their abundance is markedly elevated (25). For instance, Stevens and Kato reported a 100-fold higher ILC2 count in nasal polyps compared with controls (26). Similarly, the study by Walford et al. revealed significantly higher proportions of ILC2s in eosinophilic nasal polyps than in non-eosinophilic polyps (27).

Type 2 CRSwNP is characterized by a Th2-polarized immune response mediated by IL-4, IL-5, IL-13, and IgE, leading to eosinophilic inflammation (28). IL-4 and IL-13 activate the IL-4Rα/STAT6 signaling pathway, inducing IgE production by B cells, promoting goblet cell hyperplasia, excessive mucus secretion, and ciliary dysfunction, thereby compromising the nasal mucosal barrier and facilitating microbial colonization (29). IL-5 binds to the IL-5Rα receptor in polyps, enhancing eosinophil maturation, recruitment, and survival, which results in pronounced eosinophilic infiltration (29). IL-13 upregulates mucin gene (MUC5AC) expression, driving mucus plug formation and fibroblast activation, which contribute to tissue fibrosis (30). Elevated IL-5 levels correlate positively with CRSwNP recurrence, and eosinophils exacerbate epithelial damage via granular proteins, perpetuating a vicious inflammatory cycle (31).

Both ILC2s and Th2 cells produce type 2 cytokines. ILC2s promote Th2 cell proliferation and differentiation through surface molecules such as MHC-II, CD80, CD86, ICOS, and OX40l (12). Conversely, Th2 cells secrete IL-4 and IL-13, which directly activate ILC2s, amplifying their proliferation and enhancing cytokine production (e.g., IL-5, IL-13) (12). This creates a positive feedback loop that intensifies inflammation. In addition, ILC2-derived IL-13 and TSLP further drive dendritic cell (DC) polarization toward a Th2 phenotype, amplifying Th2 responses (32). ILC2s also suppress Treg function, disrupting immune tolerance and exacerbating Th2 inflammation (33).

As early effectors in Th2 inflammation, ILC2s are primarily activated by epithelial-derived alarmins (IL-25, IL-33, TSLP). Activated ILC2s produce IL-4, which plays a pivotal role in the early phase of Th2 inflammation by activating the STAT6 pathway and upregulating the transcription factor GATA3 (34). GATA3 further enhances the transcription of IL-4, IL-5, and IL-13 (34). IL-13 promotes the migration of activated dendritic cells from nasal polyps to draining lymph nodes, where they present antigens and prime naive CD4 T cells to differentiate into Th2 cells (35).

Crucially, emerging evidence indicates that the profibrotic activities of IL-4 and IL-13 are predominantly mediated through the dependent mechanisms of transforming growth factor-β (TGF-β). Fichtner-Feigl et al. first revealed that IL-13 directly induces TGF-β production via specific binding to IL-13Rα2 (36). This cytokine activates SMAD signaling complexes to form profibrotic transcriptional regulatory units in the nucleus (37). Concurrently, IL-4/IL-13 binding to their cognate receptors triggers transmembrane JAK kinase phosphorylation cascades, promoting STAT6 protein homodimerization and nuclear translocation, thereby amplifying the expression of both IL-4/IL-13 autocrine signals and their downstream target genes (38, 39). Notably, these two pathways exhibit significant functional synergy in the nuclear compartment: The TGF-β/SMAD system enhances promoter accessibility of fibrogenic genes [including MUC5A, Vimentin, α-SMA, Fibronectin, Collagens, and matrix metalloproteinases (MMPs)/tissue inhibitor of matrix metalloproteinases (TIMPs)] through chromatin remodeling, while the JAK/STAT pathway maintains sustained transcriptional activation via epigenetic modifications (40). The coordinated regulatory mechanism of IL-4 and IL-13 through dual TGF-β/SMAD and JAK/STAT signaling pathways ultimately leads to aberrant fibroblast proliferation, myofibroblast differentiation, and pathological deposition of extracellular matrix (ECM), thereby exacerbating the progression of tissue remodeling.

While IL-13 orchestrates dendritic cell migration and Th2 priming, additional immune checkpoints further modulate the Th2 inflammatory cascade. Notably, the programmed cell death protein 1 and programmed death-ligand 1 (PD-1/PD-L1) axis, traditionally recognized for suppressing T-cell activation in tumor immunity (41), exhibits a paradoxical proinflammatory role in CRSwNP. This context-dependent reversal of PD-1/PD-L1 function may stem from the unique Th2-skewed microenvironment, where ILC2-Th2 cell crosstalk overrides canonical immunosuppressive signaling. Specifically, PD-L1 expressed on ILC2s interacts with PD-1 on Th2 cells, creating a feedforward loop that amplifies IL-13 release and enhances Th2 cell differentiation (42). Elevated IL-33 upregulates PD-L1 via ST2 receptors on ILC2s, and through interactions with CD4T cells, further enhances GATA3 expression, thereby driving the differentiation of these T cells into IL-13-producing Th2 cells (43). Fueled by this PD-1/PD-L1-mediated Th2 amplification, a distinct PD-1highCXCR5−CD45RA−CD4+ T-cell subset expands within nasal polyps of CRSwNP patients (44). These cells secrete elevated IL-21 and express molecules critical for T–B-cell interactions, bridging innate ILC2-driven inflammation with adaptive humoral responses. Consequently, local immunoglobulin synthesis in polyps is intensified, propelling a self-reinforcing cycle of chronic inflammation.

Within immune checkpoint regulation of Th2 cascades, the PD-1/PD-L1 axis paradoxically exerts proinflammatory effects in CRSwNP. PD-L1 expressed on ILC2s interacts with PD-1 on Th2 cells, establishing a positive feedback loop that enhances IL-13 release and Th2 cell differentiation (42). IL-33 further upregulates PD-L1 through ST2 receptors on ILC2s and amplifies GATA3 expression via crosstalk with CD4T cells, driving their differentiation into IL-13-producing Th2 subsets (43).

In addition, Staphylococcus aureus superantigen invasion stimulates nasal epithelial cells to produce IgE, activates B cells to upregulate IL-4/IL-5/IL-13, and increases IL-33 production through SplD, perpetuating type 2 inflammatory mechanisms (45–47).

When nasal epithelial cells are invaded by microbes, allergens, or irritants, they release cytokines and chemokines, leading to aberrant activation of ILC2s and upregulation of type 2 inflammatory mediators in CRSwNP. Studies indicate that Th2 cytokines IL-4 and IL-13 reduce transepithelial electrical resistance (TER) and downregulate the epithelial junctional proteins (54). Soyka et al. demonstrated that IL-4 disrupts TJs structures in human nasal epithelial cells (48). Thus, allergen-triggered cascades in CRSwNP patients result in barrier disruption, inflammatory cell infiltration, and tissue remodeling.

The mucociliary system is a critical defense mechanism in the nasal cavity, maintaining airway hygiene. Barrier dysfunction is often accompanied by impaired MCC, which relies on coordinated mucus secretion by goblet cells and rhythmic ciliary motion (55). Goblet cells, interspersed among ciliated cells, secrete mucus that traps pathogens, while ciliated cells, rich in apical mitochondria, generate adenosine triphosphate (ATP) to power ciliary beating (56, 57). MCC primarily functions through the coordinated beating of ciliated epithelial cells to propel mucus across the nasal mucosal surface, trapping pathogens and other inhaled irritants (58). Therefore, dysfunctional MCC will lead to bacterial colonization, mucus accumulation, and biofilm formation. Chronic infections or irritants will upregulate IL-13 and IL-17 in nasal epithelium, promoting goblet cell hyperplasia, overexpression of MUC5AC and MUC5B mucins, and ciliary dyskinesia, ultimately driving CRSwNP (59). Ostrowski et al. further showed that mice with defective cilia develop severe CRS, underscoring the role of MCC in disease progression (60). Furthermore, multiple studies have demonstrated that impaired MCC is associated with disease progression in CRS (61–63).

TJs are the most paramount for epithelial integrity, blocking >90% of airborne particles and regulating immune cell permeability (64, 65). Soyka et al. observed TJs exhibit irregular immunofluorescence patterns, discontinuous expression, and reduced levels of proteins such as zonula occludens-1 (ZO-1) and occludin in CRSwNP (48). They also found decreased TER in nasal polyps (48), while Bernstein et al. reported elevated transepithelial potential and permeability in CRSwNP-derived epithelial cells (66). Li et al. confirmed severe TJs disruption in CRSwNP, with a marked downregulation of occludin, ZO-1, claudin-1, DSG1, and DSG2 (67). Huang et al. found reduced βIV-tubulin (a ciliary marker) and increased MUC5AC (a goblet cell marker), indicating epithelial remodeling via ciliary loss and goblet cell hyperplasia (68). In CRSwNP nasal polyps, epithelial cells exhibit thickened basement membranes, disrupted cilia, and reduced TJ protein expression, facilitating pathogen/allergen penetration and chronic inflammation (69). Altered mucus composition (MUC5AC overexpression) and ciliary dyskinesia further impair mucus clearance, perpetuating a vicious cycle of mucus retention (69). Collectively, epithelial barrier dysfunction plays a pivotal role in initiating and sustaining CRSwNP inflammation. Thus, therapies targeting epithelial repair, alongside conventional anti-inflammatory approaches, represent a promising future direction for CRSwNP management.

IL-10, a canonical Th2 cytokine, modulates M2 polarization and dampens CRSwNP inflammation by reducing antigen presentation, proinflammatory cytokine production, and macrophage bactericidal activity (92, 93). High IL-10 expression is a hallmark of M2 macrophages, which are significantly increased in nasal polyps. However, in ECRSwNP, the number of IL-10-producing M2 macrophages is reduced, and decreased IL-10 levels may contribute to the persistence of nasal mucosal inflammation (94). Consequently, M2 macrophages exhibit diminished immunosuppressive capacity due to deficient IL-10 production in ECRSwNP. While this reduction in IL-10 activity may enhance immune activation and pathogen clearance during acute severe infections, benefiting the host, it simultaneously exacerbates the development of eosinophilic inflammation (95). Macrophage migration inhibitory factor (MIF), a pleiotropic molecule highly expressed in macrophages, enhances M2 polarization and CCL-24 secretion, promoting eosinophil accumulation and worsening disease prognosis (96, 97). Elevated serum and tissue MIF levels in CRSwNP correlate with eosinophilic inflammation severity and recurrence (98).

Defective macrophage autophagy may drive ECRSwNP progression (99). Normal autophagy clears pathogens and damaged organelles, maintaining homeostasis. Choi et al. found reduced myeloid autophagy in ECRS mice, leading to eosinophilia, epithelial hyperplasia, and mucosal thickening (100). Autophagy-deficient macrophages increase IFN-γ and IL-1β, upregulating Th2 cytokines (IL-4, IL-5, IL-13) (101). Enhancing autophagy thus represents a potential therapeutic target. Finally, M2 macrophages can upregulate vascular endothelial growth factor, promoting epithelial proliferation, microvascular permeability, and polyp edema (102, 103). They also secrete MMPs, facilitating pseudocyst formation and polyp growth (104).

In summary, M2 macrophages are central players in type 2 CRSwNP, orchestrating eosinophilic inflammation, tissue remodeling, and disease recurrence through cytokine crosstalk, chemokine recruitment, and impaired resolution mechanisms (Figure 2).

Dupilumab, an inhibitor of IL-4Rα, suppresses eosinophil migration into tissues, downregulates IgE infiltration, and concurrently blocks IL-4 and IL-13 signaling pathways (116). A phase 3 clinical trial demonstrated that after 24 weeks of treatment, Dupilumab significantly reduced nasal polyp score (NPS, ≥2), nasal congestion score (NCS, ≥1), Lund–Mackay score (LMS, ≥7), and Sino-Nasal Outcome Test-22 (SNOT-22) score (≥8.9) in patients with severe CRSwNP (117). A network meta-analysis incorporating seven randomized controlled trials (RCTs) compared the efficacy and safety of biologics for CRSwNP (118). The results showed that Dupilumab outperformed benralizumab, mepolizumab, and omalizumab at 24 weeks and follow-up endpoints, demonstrating superior reductions in NPS and nasal congestion severity (118). Hopkins et al. conducted a post hoc analysis revealing that dupilumab improved CRSwNP outcomes at week 24 regardless of prior surgical history, indicating its efficacy is unaffected by previous surgeries (119). Olfactory dysfunction is a refractory feature of CRSwNP, with approximately 80% of severe cases presenting anosmia, 20% hyposmia, and fewer than 5% retaining normosmia. Studies indicate that dupilumab rapidly and significantly restores olfactory function, even reversing severe type 2 inflammation-induced anosmia (120). Matsuyama et al. found that after 24 weeks of dupilumab treatment, the circulating Th1/Th2 ratio increased compared with baseline, while PD-1-positive Tregs decreased (121). Dupilumab markedly alleviates type 2 inflammation in CRSwNP. Compared with placebo, 16 weeks of treatment significantly reduced IgE and eotaxin-3 levels in nasal secretions, as well as ECP, eotaxin-2, eotaxin-3, chemokine, IgE, and IL-13 levels in nasal polyp tissues (122). With regard to safety, dupilumab exhibited no serious adverse events (AEs) over 3 years of use in patients with atopic dermatitis (123). Overall, dupilumab represents an effective therapeutic option for patients with type 2 CRSwNP.

Mepolizumab exerts its therapeutic effects primarily by inhibiting IL-5, thereby reducing eosinophil chemotaxis, differentiation, activation, and survival (124). Previous studies have demonstrated that mepolizumab effectively treats severe eosinophilic asthma (SEA), hypereosinophilic syndrome (HES), and eosinophilic granulomatosis with polyangiitis (EGPA) by lowering circulating eosinophil levels, and it also significantly reduces dependence on systemic corticosteroids (SCC) and improves prognosis in these patients (125–127). Results from a phase 3 clinical trial indicate that mepolizumab effectively decreases circulating eosinophils, nasal polyp size, nasal congestion, systemic corticosteroid use, and the need for surgery in patients with type 2 CRSwNP (128). Following 8 weeks of mepolizumab treatment, CRSwNP patients exhibited significant reductions in blood eosinophils, serum ECP, IL-5α levels, as well as nasal secretion myeloperoxidase (MPO), periostin, IL-6, IL-1β, and IL-5Rα levels (124). As mentioned earlier, VEGF promotes edema and growth in NPs, exacerbating CRSwNP progression (103). A small-scale study (n = 12) found that mepolizumab markedly reduces VEGF, VEGFR1, and VEGFR2 expression in middle turbinate mucosa (129). Real-life studies demonstrate significant improvements in quality of life after 6 and 12 months of mepolizumab therapy, as assessed by the SNOT-22 and Rhinosinusitis Outcomes Measure-31 (RSOM-31) (130). Mepolizumab also shows efficacy in restoring olfactory function. In a cohort of severe CRSwNP patients, 22% achieved partial improvement and 14% full recovery in olfaction (131). Regarding safety, mepolizumab exhibits a favorable profile. In one real-life study, none of the 27 patients experienced AEs, while other studies reported only two cases of serious AEs (132). Thus, mepolizumab is considered a cornerstone therapy for severe type 2 CRSwNP with elevated circulating eosinophils.

Omalizumab binds to free IgE, disrupting its high-affinity interaction with FcɛRI on mast cells and basophils (133). This reduces IgE receptor expression on mast cells, basophils, and dendritic cells, thereby suppressing mediator release (133). In a randomized controlled trial involving 24 CRSwNP patients with comorbid asthma, omalizumab significantly improved NPS, LMS, and patient-reported outcomes, irrespective of allergy status (134). In addition, eosinophilic CRSwNP patients with asthma exhibited reduced peripheral blood eosinophils, fractional exhaled nitric oxide (FeNO) levels, and restored corticosteroid sensitivity following omalizumab treatment (135). In addition, a global, replicate phase III trial led by Bachert demonstrated that omalizumab add-on therapy to intranasal mometasone achieved statistically significant improvements in NPS, mean daily NCS, and patient-reported symptom severity assessments versus placebo at week 24 (all P < 0.001) (131). A real-life study reported olfactory improvement in 36% of severe asthma and CRSwNP patients treated with omalizumab (136). However, recent real-life analyses suggest a potential association between omalizumab and increased malignancy risk (137). In severe asthma populations, factors such as age, obesity, smoking, nasal polyps, and allergic rhinitis may diminish omalizumab's therapeutic efficacy (138). Anyway, evidence supporting omalizumab's efficacy in CRSwNP has been established through successful phase 3 trials (139). Omalizumab is also used for AR and other allergic conditions (140).

In addition to the approved dupilumab, mepolizumab, and omalizumab, there are still several biologics for type 2 inflammatory pathways that show potential in the treatment of CRSwNP but have not yet been approved by the FDA.

Among them, tezepelumab was the first monoclonal antibody to target TSLP, which is a product of environmental and proinflammatory stimuli and plays a key role in the initiation and persistence of airway inflammation (141). Tezepelumab by targeting TSLP, blocks the upstream signaling pathway of the inflammatory cascade, inhibiting the release of downstream type 2 inflammatory factors such as IL-4, IL-5, and IL-13, and has shown good results in severe asthma (142). A 52-week phase III trial demonstrated that subcutaneous tezepelumab 210 mg administered every 4 weeks as add-on therapy significantly reduced acute exacerbation rates and improved lung function, asthma control, and health-related quality of life compared with placebo in patients aged ≥12 years with severe asthma (143). Also, another phase III WAYPOINT trial further demonstrated that tezepelumab combined with standard therapy significantly reduced nasal polyp volume, improved olfactory loss scores (1-point reduction, P < 0.001), and decreased the proportion of patients requiring surgical intervention or systemic corticosteroids (0.5% vs. 22.1% in the placebo group) (144).

Benralizumab, an anti-IL-5 receptor alpha monoclonal antibody that induces eosinophil apoptosis, is FDA-approved for severe eosinophilic asthma and holds orphan drug status for eosinophilic EGPA (145, 146). While clinical evidence in CRSwNP remains limited, a recent Phase III trial demonstrated its efficacy, with benralizumab significantly improving NPS and NCS at week 40 compared with placebo (147).

Tralokinumab, a fully human anti-IL-13 monoclonal antibody approved for atopic dermatitis, may alleviate mucosal hyperplasia in CRSwNP by suppressing IL-13-driven inflammation, such as mucus hypersecretion and fibrosis (148). Similarly, lebrikizumab, another IL-13 inhibitor with notable efficacy in atopic dermatitis (over 50% achieving EASI-75 at 16 weeks as monotherapy), could target IL-13-mediated inflammation in CRSwNP (149).

Although these agents target key nodes in type 2 inflammation (e.g., TSLP, IL-5, IL-13) and expand possibilities for endotype-driven therapy, their efficacy and safety in CRSwNP require further clinical validation.

In recent years, clinicians have increasingly focused on the application of biologics in the treatment of CRSwNP (150). However, to date, no consensus has been reached regarding the optimal timing of administration or the selection of biologics for CRSwNP. Further research is needed to analyze additional clinical and molecular biomarkers, treatment efficacy, and adverse effects at baseline and follow-up time points, with the goal of predicting patient responses to biologic therapies in CRSwNP.