Chronic Rhinosinusitis with Nasal Polyps: Window of Immunologic Responses and Horizon of Biological Therapies

Abstract

Chronic rhinosinusitis with nasal polyps (CRSwNP) is a multifaceted inflammatory disorder characterized by distinct immunopathogenic entities, including type 2 inflammation mediated by cytokines such as interleukin-4 (IL-4), IL-5, and IL-13. These cytokines contribute to eosinophilic inflammation, epithelial barrier dysfunction, and mucus overproduction, resulting in polyp formation. Advances in molecular understanding have resulted in the identification of CRSwNP endotypes, suggesting personalized treatment approaches. Conventional therapies, such as intranasal and systemic corticosteroids, provide symptom relief but are restricted by side effects and polyp recurrence, necessitating the development of novel targeted approaches. Biologic therapies represent a breakthrough in CRSwNP management. Monoclonal antibodies such as dupilumab, omalizumab, mepolizumab, and Benralizumab (IL-5 receptor alpha) target key mediators of type 2 inflammation, leading to substantial improvements in polyp size, symptom control, and quality of life. Additionally, emerging therapies like tezepelumab and brodalumab aim to address broader immune mechanisms, including type 1 and type 3 inflammation. These advancements enable tailored treatment approaches that optimize outcomes and reduce reliance on surgical interventions. Biomarker-driven research continues to refine CRSwNP classification and treatment efficacy, emphasizing precision medicine. Future efforts should focus on expanding the therapeutic landscape, investigating long-term impacts of biologics, and exploring their combinatory potential to improve disease control. This review discusses the role of innate and adaptive immunity in the pathogenesis of CRSwNP and suggests novel cytokine-targeted strategies for further considering personalized medicine in future therapeutic plans.

1. Introduction

Chronic rhinosinusitis (CRS) is a persistent inflammatory disorder affecting the upper airways and paranasal sinuses [1]. Common clinical manifestations include nasal obstruction, mucopurulent discharge, facial pain or pressure, and a reduced sense of smell. These symptoms are often accompanied by objective evidence of inflammation, such as endoscopic findings or radiological abnormalities, to support the diagnosis [2]. CRS affects approximately 5–15% of the population, yet physician-diagnosed cases are notably lower, ranging from 2% to 4% [3,4]. This discrepancy underscores the challenges in accurate diagnosis, particularly as radiological abnormalities—frequently observed in asymptomatic individuals—are insufficient for diagnosis without corroborating clinical symptoms [5]. CRS is broadly categorized into two phenotypes based on the presence or absence of nasal polyps: CRS without nasal polyps (CRSsNP) and CRS with nasal polyps (CRSwNP). Phenotypes, such as the presence or absence of nasal polyps, offer observable clinical classifications but often fail to capture the underlying mechanisms driving disease variability. In contrast, endotypes define CRS by distinct immunological and molecular pathways—namely Th1 (interferon-gamma [IFN-γ]), Th2 (interleukin-4 [IL-4], IL-5, IL-13), and Th17 (IL-17) inflammation—each associated with specific cytokine profiles and gene expression patterns. CRSwNP is marked by type 2 inflammation, characterized by elevated levels of Th2 cytokines, leading to eosinophilic infiltration, epithelial barrier dysfunction, and tissue remodeling (Figure 1) [6,7]. In Western populations, CRSwNP is predominantly associated with type 2 inflammation, often characterized by eosinophilic infiltration and elevated IL-5, IL-4, and IL-13. However, in Asian populations, CRSwNP exhibits greater heterogeneity, with a higher prevalence of non-type 2 (e.g., neutrophilic or mixed) inflammation. Some studies have even noted a predominance of Type 1 or Type 17 cytokine profiles in CRSwNP patients from East Asia. Similarly, CRSsNP is generally associated with Th1 inflammation globally, but exceptions exist based on regional and environmental factors [8].

On the other hand, CRSwNP can be further classified into eosinophilic and non-eosinophilic subtypes, reflecting distinct inflammatory endotypes with varying contributions from immune cells [9]. Alarmins such as IL-33, IL-25, and thymic stromal lymphopoietin (TSLP) play pivotal roles in the pathogenesis of eosinophilic CRS [10]. Multivariable clustering methods combining clinical, demographic, and symptomatic data can identify subgroups predictive of treatment response, offering more refined prognostic tools than single-variable phenotypes [11]. The integration of single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics is significantly enhancing our understanding of immune cell heterogeneity and tissue remodeling in chronic CRSwNP. In uncontrolled severe CRSwNP, there is a marked shift in the nasal polyp microenvironment from epithelial and mesenchymal cell predominance to an inflammatory cell-dominated landscape, as revealed by scRNA-seq, transcriptomics, surface proteomics, and T/B cell receptor sequencing [12]. Beyond these two primary phenotypes, CRS encompasses several subtypes, including allergic fungal rhinosinusitis, aspirin-exacerbated respiratory disease, and CRS associated with cystic fibrosis or immune deficiencies, highlighting the disease’s heterogeneity [3]. Therefore, the pathogenesis of CRS is complex and involves intricate interactions between immune responses, environmental exposures, and microbial factors [13,14]. The primary objective of CRS management is to achieve clinical control, defined as minimal or no symptoms and normalization of mucosal health, typically through pharmacological and surgical interventions [6,15]. However, persistent inflammation, polyp recurrence, and treatment resistance pose significant challenges in difficult-to-treat cases. Advances in understanding the immunopathology of CRS have led to the development of biologic therapies targeting cytokines or other key mediators of type 2 inflammation. These biologics represent a paradigm shift in CRS management, offering a personalized approach for patients with refractory disease by addressing specific immunopathogenic mechanisms [16]. This review delves into the immune mechanisms underlying CRSwNP, focusing on the distinctions between eosinophilic and non-eosinophilic inflammation. Additionally, it explores the role of emerging targeted therapies, emphasizing how personalized medicine and biologic treatments are transforming CRS management and improving patient outcomes.

2. Immunopathogenesis of CRSwNP

2.1. Innate Immunity in CRSwNP

Innate immunity plays a fundamental role in the pathogenesis of CRSwNP, primarily through disruptions in the epithelial barrier and associated defense mechanisms (Table 1). The sinus epithelium serves as a critical frontline barrier, protecting the host from microbial invasion and maintaining immune homeostasis [17]. However, in CRSwNP, this barrier is frequently compromised, leading to increased permeability, chronic inflammation, and tissue remodeling. One of the key processes responsible for barrier dysfunction is epithelial-to-mesenchymal transition (EMT), during which epithelial cells lose their structural integrity and polarity, transforming into migratory mesenchymal-like cells. This process, driven by elevated levels of type 2 cytokines such as IL-4 and IL-13 in eosinophilic nasal polyps, exacerbates epithelial barrier dysfunction and contributes to the persistence of inflammation. Eosinophilic CRSwNP is characterized histologically by an infiltration of eosinophils in the nasal polyp tissue, typically defined as >10 eosinophils per high-power field (HPF), or >20% of the total inflammatory cell count. Non-eosinophilic type 2 CRSwNP refers to a less common but emerging subset, where type 2 cytokine activity is present (e.g., IL-4/IL-13 expression) without predominant eosinophilia in tissue samples.

Impaired mucociliary clearance further compounds this dysfunction, as ciliary damage and architectural abnormalities facilitate bacterial proliferation, biofilm formation, and the chronicity of inflammation [18,19]. The sinus epithelium, in collaboration with innate immune mechanisms, employs various molecular receptors and antimicrobial defenses to detect and neutralize pathogens. Among these, Toll-like receptors (TLRs) play an essential role in recognizing microbial patterns and initiating host defense responses [20]. However, research into TLR expression in CRS has produced inconsistent results, with some studies indicating elevated expression and others reporting reductions or no significant changes. Bitter taste receptors, such as T2R38, represent another important component of the innate immune response [21]. These receptors detect bacterial quorum-sensing molecules, triggering enhanced mucociliary clearance, nitric oxide (NO) production, and the release of antimicrobial peptides. Notably, functional variants of T2R38 enhance bacterial defense, whereas nonfunctional variants, like the AVI allele, are associated with more severe CRS phenotypes [22].

The complement system also contributes to pathogen elimination through mechanisms such as opsonization, chemotaxis, and membrane attack complexes (MACs). However, dysregulation of complement activation in CRS may inadvertently exacerbate inflammation and tissue damage [23]. Other key innate immune components include the LBP-BPI-PLUNC family of proteins, which play vital roles in neutralizing bacterial lipopolysaccharides (LPSs), disrupting biofilms, and eliminating pathogens. Reduced levels of PLUNC proteins have been associated with increased bacterial colonization by Staphylococcus aureus and Pseudomonas aeruginosa in CRS [22]. Similarly, acyloxyacyl hydrolase (AOAH), an enzyme involved in degrading LPSs, has been genetically linked to conditions such as asthma and CRS, highlighting its potential relevance in modulating endotoxin-driven inflammation [24]. Antimicrobial proteins also contribute significantly to epithelial defense, although their dysregulation has been observed in CRS. For instance, S100 proteins, including S100A7 and S100A8/9, exhibit antimicrobial properties but are often reduced in CRS, impairing epithelial immunity. Other key antimicrobial proteins, such as lysozyme and lactoferrin, are notably depleted in nasal polyps due to the loss of submucosal glands, further compromising local defense mechanisms [25].

Alarmins, such as IL-33 and high-mobility group box 1 protein (HMGB1), are released in response to epithelial damage and activate downstream immune responses. IL-33, in particular, plays a pivotal role in amplifying type 2 inflammation by activating mast cells, dendritic cells, and group 2 innate lymphoid cells (ILC2s) [26]. These ILC2s are key drivers of eosinophilic inflammation in CRSwNP, producing IL-5 and IL-13, which perpetuate chronic inflammation and disrupt mucosal integrity. In contrast, neutrophils, which are predominantly implicated in non-eosinophilic CRS, combat pathogens by releasing neutrophil extracellular traps (NETs). While NETs are effective in neutralizing biofilms, their overproduction can exacerbate local inflammation and tissue damage [14]. A major challenge in CRS management is the presence of biofilms, particularly those formed by Staphylococcus aureus and Pseudomonas aeruginosa. These biofilms are highly resistant to host immune responses and antibiotic therapies, contributing to persistent inflammation and treatment refractoriness. The chronic presence of biofilms not only sustains the inflammatory environment but also hinders the efficacy of pharmacological interventions, emphasizing the need for innovative therapeutic strategies targeting biofilm disruption [13].

The innate immune system, mainly pattern recognition receptors (PRRs), plays a significant role in this condition. PRRs, like TLRs and nucleotide-binding oligomerization domain-like receptors (NLRs), are very important for recognizing pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) [27]. The nose epithelium acts as a first line of defense and has many PRRs that can find microbes and start a chain of events that cause inflammation. For example, TLRs help cells recognize parts of bacteria like lipopolysaccharides and peptidoglycans, which sets off signaling pathways further down the line, such as the NF-κB pathway. When this happens, pro-inflammatory cytokines and chemokines are made. These play a key role in controlling the immune reaction in CRS [28]. The NLRP3 inflammasome has also been linked to CRS. It is a part of the natural immune system that reacts to cellular stress and infection. When the NLRP3 inflammasome is activated in nasal epithelial cells, it can cause IL-1β to be released, which is a potent cytokine that worsens inflammation in CRS [29].

This means that PRRs not only start the immune reaction, but they also help keep the chronic inflammation that is a feature of CRS going. New studies have also shown that the microbiome affects the immune system in people with CRS. Dysbiosis, or an unbalance in the microbial communities in the sinonasal cavity, can change how PRRs are expressed and work, which makes the inflammatory environment of CRS even more complicated. For instance, some bacteria, like Staphylococcus aureus, can turn on PRRs, which can make inflammatory reactions stronger and make CRS symptoms last longer [30]. Monocytes are an essential part of innate and adaptive immune reactions and play a big part in CRS pathophysiology. These cells help make macrophages and dendritic cells and play a part in the inflammatory processes that make up CRS. Some of the things they do are phagocytosis, antigen presentation, and secretion of pro-inflammatory cytokines, which can make the inflammatory reaction in the sinonasal mucosa worse. In CRSwNP, especially the eosinophilic form (eCRSwNP), monocytes are drawn to the site of inflammation and can change into macrophages, which keep the inflammation going. High numbers of monocytes and macrophages have been found in the sinonasal tissues of people with CRS, which suggests that they play a part in the local immune reaction [31]. These cells can make cytokines like IL-1, IL-6, and tumor necrosis factor-alpha (TNF-α), which are essential for getting other immune cells like eosinophils and T lymphocytes to the area, which makes the inflammatory reaction stronger. In addition, how monocytes and other immune cells interact is very important in creating the immune landscape of CRS. One example is that monocytes can change the differentiation and stimulation of T cells by releasing cytokines and showing antigens. This relationship is significant regarding Th2-mediated inflammation, which is common in CRSwNP. Changes in monocyte function, such as less phagocytic activity and different cytokine release, have been linked to the disease lasting long [32]. Some new studies have also examined how environmental factors, like not getting enough vitamin D, might affect the activity of monocytes in CRS. Vitamin D affects how the immune system works. Not getting enough of it has been linked to more monocyte activation and a more vigorous inflammatory reaction in people with CRS. This means that lowering vitamin D levels might help treat CRS by changing the activity of monocytes and, in turn, the inflammatory processes in the disease [33].

Table 1. Key components of innate immunity in CRSwNP.

Category	Component	Function	Dysregulation in CRSwNP	Ref.
Barrier Integrity	Epithelial Barrier	Prevents entry of antigens.	Increased permeability, EMT, and tissue remodeling driven by IL-4 and IL-13.	[18,19]
	Mucociliary Clearance	Clears mucus and microbes from nasal passages.	Ciliary dysfunction and abnormal ciliogenesis allow bacterial proliferation and biofilm formation.	[22]
Pattern Recognition Receptor	Toll-like Receptors (TLRs)	Recognize microbial patterns and initiate inflammatory responses.	Inconsistent expression levels, leading to variable immune responses.	[20,21]
	Bitter Taste Receptors (T2R38)	Detect quorum-sensing molecules and trigger mucociliary clearance and antimicrobial peptide release.	Nonfunctional T2R38 alleles linked to severe disease and reduced antimicrobial responses.	[22]
	LBP-BPI-PLUNC Proteins	Bind LPS and disrupt bacterial biofilms.	Reduced PLUNC levels in eosinophilic polyps, correlating with colonization by S. aureus and P. aeruginosa.	[22]
	Acyloxyacyl Hydrolase (AOAH)	Degrades bacterial LPS and modulates inflammation.	Genetically linked to CRS and asthma.	[24]
Antimicrobial Defense	S100 Proteins	Exhibit antimicrobial and inflammatory-modulating properties.	Decreased levels of S100A7 and S100A8/9 in CRS patients, leading to impaired epithelial defense.	[25]
	Lysozyme and Lactoferrin	Protect against bacterial infections.	Reduced in nasal polyp tissues due to submucosal gland loss, compromising local defense.	[25]
Resident Immune Cells	Neutrophils	Combat pathogens through NETs and enzymatic activity.	Contribute to biofilm resistance and chronic inflammation in non-eosinophilic CRS.	[14]
	ILC2s	Produce IL-5 and IL-13, driving type 2 inflammation.	Increased numbers of eosinophilic CRS, amplifying inflammation and eosinophil recruitment.	[26]
Alarmins	IL-33, HMGB1	Activate mast cells, dendritic cells, and ILC2s to amplify immune responses.	Elevated levels drive type 2 inflammation and epithelial damage.	[26]
Complement System	Complement Proteins	Enhance pathogen clearance through opsonization and MAC formation.	Dysregulation may contribute to chronic inflammation and impaired microbial control.	[13]
Biofilms	Pathogenic Biofilms	Protect bacteria from host defenses and antibiotics.	Biofilms by S. aureus and P. aeruginosa perpetuate inflammation and treatment resistance.	[13]

Table 1. Key components of innate immunity in CRSwNP.

Category	Component	Function	Dysregulation in CRSwNP	Ref.
Barrier Integrity	Epithelial Barrier	Prevents entry of antigens.	Increased permeability, EMT, and tissue remodeling driven by IL-4 and IL-13.	[18,19]
	Mucociliary Clearance	Clears mucus and microbes from nasal passages.	Ciliary dysfunction and abnormal ciliogenesis allow bacterial proliferation and biofilm formation.	[22]
Pattern Recognition Receptor	Toll-like Receptors (TLRs)	Recognize microbial patterns and initiate inflammatory responses.	Inconsistent expression levels, leading to variable immune responses.	[20,21]
	Bitter Taste Receptors (T2R38)	Detect quorum-sensing molecules and trigger mucociliary clearance and antimicrobial peptide release.	Nonfunctional T2R38 alleles linked to severe disease and reduced antimicrobial responses.	[22]
	LBP-BPI-PLUNC Proteins	Bind LPS and disrupt bacterial biofilms.	Reduced PLUNC levels in eosinophilic polyps, correlating with colonization by S. aureus and P. aeruginosa.	[22]
	Acyloxyacyl Hydrolase (AOAH)	Degrades bacterial LPS and modulates inflammation.	Genetically linked to CRS and asthma.	[24]
Antimicrobial Defense	S100 Proteins	Exhibit antimicrobial and inflammatory-modulating properties.	Decreased levels of S100A7 and S100A8/9 in CRS patients, leading to impaired epithelial defense.	[25]
	Lysozyme and Lactoferrin	Protect against bacterial infections.	Reduced in nasal polyp tissues due to submucosal gland loss, compromising local defense.	[25]
Resident Immune Cells	Neutrophils	Combat pathogens through NETs and enzymatic activity.	Contribute to biofilm resistance and chronic inflammation in non-eosinophilic CRS.	[14]
	ILC2s	Produce IL-5 and IL-13, driving type 2 inflammation.	Increased numbers of eosinophilic CRS, amplifying inflammation and eosinophil recruitment.	[26]
Alarmins	IL-33, HMGB1	Activate mast cells, dendritic cells, and ILC2s to amplify immune responses.	Elevated levels drive type 2 inflammation and epithelial damage.	[26]
Complement System	Complement Proteins	Enhance pathogen clearance through opsonization and MAC formation.	Dysregulation may contribute to chronic inflammation and impaired microbial control.	[13]
Biofilms	Pathogenic Biofilms	Protect bacteria from host defenses and antibiotics.	Biofilms by S. aureus and P. aeruginosa perpetuate inflammation and treatment resistance.	[13]

2.1.1. Eosinophils

Eosinophilic and non-eosinophilic CRSwNP represent distinct inflammatory subtypes with different immunopathological mechanisms and clinical implications. Eosinophilic CRSwNP is predominantly characterized by type 2 inflammation, driven by elevated levels of cytokines such as IL-4, IL-5, and IL-13 [34,35]. These cytokines play critical roles in sustaining eosinophil activation and prolonging their survival, promoting tissue damage through the release of cytotoxic granules and inflammatory mediators. The severity of eosinophilic inflammation is strongly associated with biomarkers such as periostin, which reflects the underlying type 2 immune response [36]. Additionally, disruptions in epithelial barrier integrity, exacerbated by histone deacetylase activity and the enhanced production of IL-13 and prostaglandin D2 (PGD2) via secretory phospholipase A2 group IIB (sPLA2GIB), contribute to the persistence and amplification of eosinophilic inflammation [23,37]. In contrast, non-eosinophilic CRSwNP is characterized by a Th1/Th17 immune response, with a predominant infiltration of neutrophils and elevated levels of pro-inflammatory cytokines such as IL-17 and TNF-α [36,37]. Neutrophil-dominant inflammation is often associated with chronic bacterial infections, which perpetuate local immune activation. Elevated levels of calprotectin serve as a hallmark of neutrophil activity in this subtype [38]. Chemokines play a pivotal role in the recruitment of eosinophils to inflammatory sites in eosinophilic CRSwNP. The CCR3 receptor, predominantly expressed on eosinophils, interacts with a range of chemokines, including MCP-4 (CCL13), RANTES (CCL5), and the eotaxins (CCL11, CCL24, and CCL26) [39]. Elevated levels of eotaxin-1, -2, and -3 have been observed in eosinophilic nasal polyps, correlating strongly with eosinophil accumulation and the progression of inflammation. These chemokine-driven mechanisms underscore the central role of eosinophil recruitment in the pathogenesis of eosinophilic CRSwNP and offer potential therapeutic targets for managing this subtype [40,41]. The distinct immunopathological mechanisms underlying eosinophilic and non-eosinophilic CRSwNP have paved the way for the development of targeted therapies tailored to the specific inflammatory patterns of each subtype [42,43]. Additionally, external factors like smoking have been shown to alter immune responses, exacerbating local inflammation and highlighting the interplay between environmental triggers and innate immune mechanisms. Non-eosinophilic CRSwNP also involves autoantibody production and dysregulated local immunoglobulin E (IgE) synthesis, suggesting a complex interaction between innate and adaptive immune pathways [44].

2.1.2. Mast Cells

Mast cells are crucial in immune defense, tissue repair, and allergic inflammation. They express high-affinity IgE receptors (FcεRI), which, when cross-linked by IgE-allergen interactions, trigger degranulation and release mediators like histamine and proteases. Additionally, they produce cytokines such as IL-4, IL-5, and IL-13, along with prostaglandins and leukotrienes, sustaining type 2 inflammation [45,46]. In eCRSwNP, mast cells are prevalent in the nasal epithelium, particularly in polyp tissue, where they interact closely with eosinophils. This interaction drives type 2 inflammation, worsening symptoms. Mast cells promote eosinophil survival and activation through IL-4 and IL-13, creating a feedback loop that amplifies inflammation. Environmental allergens exacerbate these processes via IgE-mediated reactions, underscoring mast cells’ central role in eCRSwNP [47,48,49]. They also respond to epithelial-derived cytokines like IL-1, IL-33, and TSLP, enhancing activation and contributing to eosinophilic inflammation during viral infections or allergen exposure [38,50]. Studies suggest that epithelial cells may directly activate intraepithelial mast cells through cytokines like TSLP and IL-1, especially in type 2 inflammatory environments [51,52]. Mast cells contribute to chronic inflammation by releasing IL-5, promoting eosinophil recruitment, and TSLP, which primes dendritic cells for Th2 differentiation. Elevated levels of TSLP and type 2 cytokines in nasal tissues of eCRSwNP patients highlight their role in sustaining inflammation [53,54,55,56].

In CRS, particularly eCRSwNP, mast cells are strategically located in the sinonasal mucosa and are pivotal in chronic inflammation and tissue remodeling. They release cytokines like IL-5, crucial for eosinophil activation and survival, alongside GM-CSF and eotaxin [57]. These mediators perpetuate eosinophilic inflammation and facilitate the influx of other immune cells, maintaining chronic inflammation. Research indicates that mast cells in CRSwNP exhibit phenotypic changes associated with increased IgE production and eosinophilia, suggesting their active role in allergic reactions [58]. Degranulation releases preformed mediators like histamine, tryptase, and chymase, contributing to acute inflammatory responses and symptoms like nasal congestion and mucosal swelling. The extent of mast cell degranulation correlates with disease severity and eosinophil counts in tissues. Mast cells also communicate with other immune cells, including T cells and eosinophils, through surface receptors and cytokines, intensifying the inflammatory response [59]. New findings reveal that mast cells can be activated by factors like enterotoxins from Staphylococcus aureus, leading to polyclonal IgE production and persistent inflammation. This long-term activation positions mast cells as potential therapeutic targets. Moreover, immune checkpoint receptors like TIM-3 on mast cells may influence their function in chronic inflammatory conditions such as CRSwNP, indicating their regulatory roles in the immune environment [60].

2.1.3. ILC2 Cells

Innate lymphoid cells (ILCs) are a unique subset of immune cells characterized by their lack of antigen receptors and lineage markers. They are activated by innate immune signals, including cytokines and pathogens, and are classified into three subsets: ILC1, ILC2, and ILC3 [61]. ILC2s are particularly notable for producing type 2 cytokines such as IL-5 and IL-13. First identified by Fort et al. in 2001 [62], ILC2s have been recognized in mice since 2010 and are also known as nuocytes or natural helper cells. ILC2s express receptors for IL-33 and TSLP, which stimulate type 2 cytokine production. While IL-33 and TSLP each have modest effects individually, their combination significantly enhances cytokine production in ILC2s isolated from peripheral blood and nasal polyps (NPs) [63,64]. This suggests that ILC2s contribute to local type 2 inflammation in eosinophilic NPs by responding to these cytokines.

A key marker for human ILC2s is CRTH2, a chemokine receptor that attracts Th2 cells, eosinophils, and basophils [65]. Mast cells also release pro-allergic mediators, such as cysteinyl leukotrienes (CysLTs), during degranulation, which can further stimulate ILC2s. Research shows that CysLTR1 on ILC2s responds to LTC4 and LTD4, enhancing type 2 cytokine production [66]. Given the abundance and activation of mast cells in eosinophilic NPs, their degranulation may amplify ILC2 recruitment and cytokine production through the release of PGD2 and CysLTs [67,68]. ILC2s are activated by cytokines released during allergic responses, leading to the production of IL-4, IL-5, and IL-13, which are crucial for sustaining eosinophilic inflammation in conditions like CRSwNP [69]. These cytokines facilitate eosinophil survival and recruitment. Blocking IL-4 and IL-13 has been shown to reduce ILC2 proliferation in sinonasal tissues [70]. Additionally, ILC2s play a role in IgE production, supporting allergic responses and perpetuating the type 2 inflammatory cycle in CRSwNP [71].

2.1.4. NK Cells

Natural killer (NK) cells are essential components of the innate immune system, particularly in the context of eCRSwNP. They identify and eliminate infected or abnormal cells while modulating immune responses through cytokine secretion [72]. NK cells produce interferon-gamma (IFN-γ), which inhibits eosinophil activation and survival, thereby helping to maintain sinonasal mucosal integrity and reduce inflammation. A loss of NK cells has been linked to increased eosinophilia in experimental models of CRS, emphasizing their regulatory role in eosinophilic inflammation [73]. Beyond their cytotoxic functions, NK cells interact with other immune cells, such as dendritic cells (DCs) and T cells, enhancing T cell activation and strengthening the adaptive immune response. However, in chronic inflammatory conditions like CRS, NK cells may become dysfunctional, exhibiting altered cytokine production and reduced cytotoxic activity, which exacerbates inflammation [74,75]. Environmental factors, such as elevated prostaglandin D2 (PGD2) levels, can impair NK cell function, further promoting eosinophilic inflammation. This complex interplay between NK cells and the inflammatory environment in CRS suggests that targeting NK cell dysfunction could be a promising therapeutic strategy for ECRSwNP [76].

2.2. Adaptive Immunity in CRSwNP

The adaptive immune system plays a central role in the pathogenesis of CRSwNP, orchestrating antigen-specific responses and immunological memory that contribute to the chronic inflammatory environment. Central to adaptive immunity in CRSwNP are T cells and B cells, which coordinate complex immune pathways that influence disease severity and persistence (Table 2). The interactions between these cells, their cytokine profiles, and antigen-presenting cells such as dendritic cells further highlight the intricate immune mechanisms at play [77].

2.2.1. T Helper Cells

CD4+ helper T cells play a pivotal role in regulating immune responses in CRSwNP. They differentiate into various subsets, including Th1, Th2, Th9, Th17, and Th22, each contributing uniquely to inflammation. The differentiation into T-helper 2 (Th2) cells is significantly influenced by IL-4, initiating a type 2 immune response. Elevated levels of IL-4 correlate with increased eosinophil activation and survival, contributing to the chronic inflammation observed in eosinophilic CRSwNP [78]. IL-4 also promotes the production of immunoglobulin E (IgE), a key player in allergic responses [79]. Recent studies have highlighted a connection between IL-4 and Ki-67 in nasal polyp tissue, suggesting IL-4’s involvement in tissue cell proliferation. Eosinophils rely on IL-5 for survival and differentiation, with high IL-5 levels frequently found in the nasal tissues of eCRSwNP patients, leading to eosinophilic congestion. Monoclonal antibodies targeting IL-5 have shown efficacy in reducing eosinophil levels and improving clinical outcomes in eCRSwNP [80]. IL-13, similar to IL-4, promotes mucus production and epithelial cell proliferation, contributing to nasal obstruction. Increased IL-13 levels in patients correlate with symptom severity [81].

Epithelial-derived cytokines such as IL-25, IL-33, and TSLP are critical in driving local type 2 immune responses. Elevated levels of these cytokines are associated with type 2 inflammatory diseases, including atopic dermatitis and asthma. IL-25 and IL-33 are particularly involved in promoting innate type 2 inflammatory responses. IL-25, a member of the IL-17 cytokine family, is distinct from other IL-17 family members in that it fosters type 2 inflammation, including eosinophilia, even in Rag2-deficient mice [82,83,84]. It also promotes type 2 cytokine production in memory Th2 cells, basophils, and ILC2s. However, studies show low mRNA levels of IL-25 in sinus tissues, indicating limited expression in CRSwNP. IL-25R is present on memory Th2 cells, basophils, and ILC2s, and IL-25 promotes the production of type 2 cytokines in these cell types. In the context of CRS, only a limited number of studies have explored the expression of IL-25. One study found that mRNA levels of IL-25 were very low in sinus tissues, with similar IL-25 mRNA expression observed in both NPs and control sinus tissues (unpublished data). IL-33, the most recent member of the IL-1 cytokine family, is known to trigger type 2 inflammation. The production of IL-33 is regulated by innate immune signaling pathways, including those mediated by P2 purinergic receptors [85]. IL-33, known for triggering type 2 inflammation, transduces signals through a heterodimer receptor including IL-1RL1 (ST2) and IL-1RAcP. Although IL-33 induces type 2 inflammation in rag-deficient mice, its levels are not significantly elevated in CRSwNP [86,87]. TSLP, a cytokine similar to IL-7, drives both innate and adaptive type 2 immune responses. Its production is influenced by immune signals, including Toll-like receptor activation. TSLP has a well-documented pathogenic role in CRSwNP, indicating its potential as a therapeutic target for managing eosinophilic NPs [55,88]. Unlike IL-25 and IL-33, TSLP has consistently been shown to have a pathogenic role in CRSwNP. Given that TSLP may regulate type 2 inflammation in eosinophilic NPs, targeting TSLP could potentially emerge as a therapeutic strategy for CRSwNP in the future. According to the current literature, TSLP may serve as a crucial regulator of type 2 immunity in eosinophilic NPs. While IL-33 may contribute to inflammation, it is not elevated in CRS [87]. Tregs, characterized by FoxP3 expression, are essential for maintaining immune tolerance and modulating inflammation. In CRSwNP patients, Treg populations are reduced, exhibiting impaired migration and decreased transforming growth factor beta (TGF-β) production. The overexpression of suppressor of cytokine signaling 3 (SOCS3) in Tregs disrupts their function, contributing to an imbalance between pro-inflammatory and anti-inflammatory cytokines [89,90]. In contrast, non-eosinophilic CRSwNP is characterized by Th1- and Th17-mediated neutrophilic inflammation. Th17 cells secrete cytokines like IL-17A, IL-17F, and IL-22, which recruit neutrophils and exacerbate tissue remodeling. While IL-22 promotes epithelial repair, it also amplifies inflammatory responses. Interestingly, IL-21, another Th17-derived cytokine, may exert protective effects by modulating Th2 inflammation, highlighting the complex interplay of T cell subsets in CRSwNP [91,92].

2.2.2. B Cells

B cells play a crucial role in the pathogenesis of CRSwNP through immunoglobulin production and antibody-mediated inflammation [93]. In nasal polyps, there are elevated levels of B cell-activating factor (BAFF) and increased expression of B cell markers like CD19 and plasma cell marker CD138, indicating heightened B cell activity and differentiation into antibody-secreting plasma cells. These B cells undergo local class switch recombination, producing various immunoglobulin isotypes, including IgE, IgA, and IgG [94]. IgE-mediated allergic responses are particularly significant in eosinophilic CRSwNP, where interactions between Th2 cells and B cells promote IgE class switching, amplifying type 2 inflammation and driving eosinophilic infiltration and epithelial damage. Elevated IgE levels correlate strongly with disease severity. Recent studies have also identified soluble IgD (sIgD) and IgD⁺ plasmablasts in nasal tissues, indicating their potential as biomarkers for disease severity, especially in non-eosinophilic CRSwNP [95]. The interplay between Th2 cells and B cells is essential for sustaining type 2 inflammation in CRSwNP. Th2 cytokines such as IL-4, IL-5, and IL-13 enhance B cell differentiation and IgE production, creating a self-perpetuating cycle of chronic inflammation that exacerbates eosinophilic CRSwNP and highlights potential therapeutic targets for modulating these immune pathways [94,95].

2.2.3. Dendritic Cells

Dendritic cells (DCs) are crucial antigen-presenting cells that connect innate and adaptive immunity by presenting antigens to T cells and influencing T helper cell responses [96]. In CRSwNP, myeloid dendritic cells (mDCs) are particularly significant in promoting type 2 inflammation. Subtypes such as mDC1 and mDC2 are recruited to nasal polyp tissues through chemokines like CCL18 and CCL23. Notably, mDC2s express OX40 ligand (OX40L) and TSLP receptors, facilitating the differentiation of naïve T cells into Th2 cells [97]. These interactions amplify the Th2-dominant environment observed in eosinophilic CRSwNP. This Th2 polarization is mediated through the release of key cytokines, such as IL-4, IL-5, and IL-13. These cytokines not only recruit eosinophils but also activate them, contributing to sustained inflammation, tissue remodeling, and the clinical features of CRSwNP, including polyp formation and airway obstruction. IL-4 plays a critical role in amplifying the Th2 response by promoting the differentiation of naive CD4+ T cells into Th2 cells. Additionally, IL-4 induces immunoglobulin class switching in B cells to produce IgE, which facilitates mast cell activation and perpetuates the inflammatory cascade. IL-5 is crucial for eosinophil activation, recruitment, and survival, enabling these cells to release cytotoxic granules and pro-inflammatory mediators, which exacerbate tissue damage and remodeling in the sinonasal mucosa. IL-13 contributes to epithelial barrier dysfunction by disrupting tight junctions and increasing mucin production, further impairing sinonasal function and promoting a chronic inflammatory state [98]. Plasmacytoid dendritic cells (pDCs), while less extensively studied, are involved in antiviral immunity and may influence the balance between type 1 and type 2 immune responses. The interaction of epithelial-derived factors like TSLP and IL-33 with dendritic cells underscores the complexity of immune regulation in CRSwNP [99].

Table 2. Key components of adaptive immunity in CRSwNP.

Category	Component	Function	Dysregulation in CRSwNP	Therapeutic Implications	Ref.
T Cells	Th1 Cells	Produce IFN-γ, driving cell-mediated immunity and antimicrobial responses.	Reduced activity in eosinophilic CRSwNP, but may contribute to neutrophilic inflammation in non-eosinophilic CRSwNP.	Targeting IFN-γ pathways for non-eosinophilic CRSwNP.	[77]
	Th2 Cells	Release IL-4, IL-5, IL-13, promoting type 2 inflammation and eosinophilic infiltration.	Dominant in eosinophilic CRSwNP; linked to tissue damage, mucus production, and epithelial barrier dysfunction.	Biologic therapies targeting IL-4Rα (dupilumab), IL-5 (mepolizumab, reslizumab).	[77]
	Th17 Cells	Secrete IL-17A, IL-17F, and IL-22, driving neutrophilic recruitment and tissue remodeling.	Elevated in non-eosinophilic CRSwNP; IL-21 alterations may impact allergic inflammation.	Anti-IL-17 therapies (e.g., secukinumab) for neutrophilic inflammation.	[100]
	Th9 Cells	Produce IL-9, promoting epithelial growth and inflammatory cell infiltration.	Increased IL-9 and IL-9R expression in epithelial and submucosal cells in CRSwNP.	Targeting IL-9 to reduce epithelial overgrowth and inflammation.	[100]
	Th22 Cells	Secrete IL-22, contributing to epithelial repair and inflammation.	Elevated IL-22 levels linked to eosinophilic inflammation and reduced IL-22 receptor expression in CRSwNP.	Modulation of IL-22 pathways for epithelial repair and inflammation control.	[77,100]
	T Regulatory (Treg) Cells	Suppress immune responses, maintain tolerance, and regulate inflammation.	Reduced Treg populations, impaired migration, and overexpression of SOCS3 inhibiting FoxP3 expression.	SOCS3 inhibitors and TGF-β supplementation to restore Treg function.	[89,90]
Dendritic Cells	Myeloid DCs (mDC1, mDC2)	Present antigens, modulate Th responses (mDC1: Th2 polarization; mDC2: Th17 polarization).	mDC2 abundance promotes Th2 dominance; mDC1s in lamina propria enhance type 2 cytokine production via OX40L.	Blocking TSLP-OX40L pathways to reduce Th2 inflammation.	[97]
	Plasmacytoid DCs (pDCs)	Regulate type 1 and type 2 immune responses and antiviral defense.	Limited role identified in CRSwNP but may regulate inflammation balance.	Enhancing pDC function to counteract type 2 inflammation.	[99]
B Cells	BAFF (B cell-activating factor)	Supports B cell survival, differentiation, and Ig production.	Elevated BAFF levels in nasal polyps, promoting plasma cell differentiation and IgE production.	Targeting BAFF to suppress B cell activity and Ig production.	[94]
	Plasma Cells	Fully differentiated B cells that secrete immunoglobulins.	Increased plasma cells producing IgE, IgA, IgM, and soluble IgD in nasal polyps.	Suppression of local IgE and antibody production.	[94]
	IgE	Amplifies type 2 inflammation via mast cell activation and eosinophilic recruitment.	Elevated IgE levels correlate with eosinophilic CRSwNP severity.	Anti-IgE therapies (e.g., omalizumab) to reduce type 2 inflammation.	[95]
	IgD+ Plasmablasts	Contribute to local inflammation via soluble IgD production.	Increased levels in non-eosinophilic CRSwNP; role in local immune responses.	Investigation of IgD-targeted therapies for non-eosinophilic CRSwNP.	[95]

Table 2. Key components of adaptive immunity in CRSwNP.

Category	Component	Function	Dysregulation in CRSwNP	Therapeutic Implications	Ref.
T Cells	Th1 Cells	Produce IFN-γ, driving cell-mediated immunity and antimicrobial responses.	Reduced activity in eosinophilic CRSwNP, but may contribute to neutrophilic inflammation in non-eosinophilic CRSwNP.	Targeting IFN-γ pathways for non-eosinophilic CRSwNP.	[77]
	Th2 Cells	Release IL-4, IL-5, IL-13, promoting type 2 inflammation and eosinophilic infiltration.	Dominant in eosinophilic CRSwNP; linked to tissue damage, mucus production, and epithelial barrier dysfunction.	Biologic therapies targeting IL-4Rα (dupilumab), IL-5 (mepolizumab, reslizumab).	[77]
	Th17 Cells	Secrete IL-17A, IL-17F, and IL-22, driving neutrophilic recruitment and tissue remodeling.	Elevated in non-eosinophilic CRSwNP; IL-21 alterations may impact allergic inflammation.	Anti-IL-17 therapies (e.g., secukinumab) for neutrophilic inflammation.	[100]
	Th9 Cells	Produce IL-9, promoting epithelial growth and inflammatory cell infiltration.	Increased IL-9 and IL-9R expression in epithelial and submucosal cells in CRSwNP.	Targeting IL-9 to reduce epithelial overgrowth and inflammation.	[100]
	Th22 Cells	Secrete IL-22, contributing to epithelial repair and inflammation.	Elevated IL-22 levels linked to eosinophilic inflammation and reduced IL-22 receptor expression in CRSwNP.	Modulation of IL-22 pathways for epithelial repair and inflammation control.	[77,100]
	T Regulatory (Treg) Cells	Suppress immune responses, maintain tolerance, and regulate inflammation.	Reduced Treg populations, impaired migration, and overexpression of SOCS3 inhibiting FoxP3 expression.	SOCS3 inhibitors and TGF-β supplementation to restore Treg function.	[89,90]
Dendritic Cells	Myeloid DCs (mDC1, mDC2)	Present antigens, modulate Th responses (mDC1: Th2 polarization; mDC2: Th17 polarization).	mDC2 abundance promotes Th2 dominance; mDC1s in lamina propria enhance type 2 cytokine production via OX40L.	Blocking TSLP-OX40L pathways to reduce Th2 inflammation.	[97]
	Plasmacytoid DCs (pDCs)	Regulate type 1 and type 2 immune responses and antiviral defense.	Limited role identified in CRSwNP but may regulate inflammation balance.	Enhancing pDC function to counteract type 2 inflammation.	[99]
B Cells	BAFF (B cell-activating factor)	Supports B cell survival, differentiation, and Ig production.	Elevated BAFF levels in nasal polyps, promoting plasma cell differentiation and IgE production.	Targeting BAFF to suppress B cell activity and Ig production.	[94]
	Plasma Cells	Fully differentiated B cells that secrete immunoglobulins.	Increased plasma cells producing IgE, IgA, IgM, and soluble IgD in nasal polyps.	Suppression of local IgE and antibody production.	[94]
	IgE	Amplifies type 2 inflammation via mast cell activation and eosinophilic recruitment.	Elevated IgE levels correlate with eosinophilic CRSwNP severity.	Anti-IgE therapies (e.g., omalizumab) to reduce type 2 inflammation.	[95]
	IgD+ Plasmablasts	Contribute to local inflammation via soluble IgD production.	Increased levels in non-eosinophilic CRSwNP; role in local immune responses.	Investigation of IgD-targeted therapies for non-eosinophilic CRSwNP.	[95]

2.3. Therapeutic Approaches for CRSwNP: Past, Ongoing, and Future Clinical Directions

The foundation of CRSwNP management includes traditional pharmacotherapy, such as intranasal corticosteroids (INCS), which effectively manage symptoms and polyp size. For severe cases, systemic corticosteroids and adjunctive treatments are utilized, though their long-term use is limited due to potential side effects [101]. Surgical interventions, particularly endoscopic sinus surgery (ESS), are common for refractory cases but often face challenges with polyp recurrence [102]. Future CRS treatments are moving toward personalized, endotype-based care, driven by advances in immune pathway understanding and targeted therapies to reduce the need for surgical interventions [58]. Mucus-based endotyping plays a major role, offering a minimally invasive, repeatable method to monitor disease using biomarkers such as IL-4, IL-5, IL-13, IL-17A, TLSP, cystatins, and periostin, which are associated with disease severity and outcomes [11]. Non-eosinophilic CRSwNP requires tailored approaches that target neutrophil-dominant inflammation. Anti-IL-17 therapies and anti-TNF therapies address Th1/Th17-mediated immune responses, while long-term antibiotic therapy may help manage chronic bacterial infections and biofilm-related complications [103]. Multivariable clustering approaches integrating clinical and symptomatic data offer improved patient stratification and prediction of biologic response in CRSwNP. Additionally, single-cell RNA sequencing and spatial transcriptomics are uncovering immune cell heterogeneity and inflammation-driven tissue remodeling in severe, treatment-resistant cases [12]. The emergence of biologic therapies has revolutionized the treatment landscape for CRSwNP, particularly for patients with persistent disease or those who fail to respond to conventional therapies. These biologics are designed to disrupt specific components of the type 2 inflammatory cascade that underpins the pathogenesis of CRSwNP, offering precision treatment tailored to the underlying immunological mechanisms [104]. Although current biologics—such as dupilumab, omalizumab, mepolizumab, reslizumab, and benralizumab—have shown substantial efficacy in eosinophilic, type 2-dominant CRSwNP, emerging approaches aim to broaden the therapeutic scope beyond this subset. Novel agents targeting upstream alarmins like TSLP (e.g., tezepelumab, CM326) and IL-17 pathways (e.g., brodalumab) offer promise for modulating early immune activation and addressing neutrophilic or mixed endotypes. Future research should prioritize head-to-head biologic comparisons, combination therapies targeting multiple cytokine axes, and long-term studies evaluating effects on epithelial remodeling and disease progression. The integration of minimally invasive tools like mucus-based endotyping and real-time biomarker monitoring may further enhance treatment personalization. Collectively, these directions underscore a shift toward precision medicine in CRSwNP, aiming to improve outcomes, reduce reliance on surgery, and address currently unmet needs in non-type 2 inflammatory phenotypes [105]. Despite their promising efficacy, biologic therapies have some limitations. The high cost of treatment poses a significant barrier to widespread access and long-term use, especially in healthcare systems with limited reimbursement frameworks. Furthermore, the optimal duration of biologic therapy remains unclear, and evidence suggests that discontinuation may lead to relapse in some patients, necessitating ongoing maintenance strategies. Biologics that target key immune pathways may also carry theoretical risks of impairing host defense mechanisms, potentially increasing susceptibility to infections, or altering immune surveillance. Long-term safety data are still evolving, and further studies are needed to clarify the risk–benefit profile, determine patient selection criteria, and assess cost-effectiveness over time. In the following, we discuss new biologic therapies for CRSwNP (Table 3).

2.4. Targeting Key Cytokines with Monoclonal Antibodies

2.4.1. IgE Blockade

Omalizumab is approved for the management of severe allergic asthma in patients who do not respond adequately to conventional asthma treatments, with IgE serum levels ranging from 30 to 1500 kU/L. Elevated total IgE levels have been observed in nasal secretions, polyp tissue, and serum of patients with CRSwNP, similar to the findings in asthma. It has now been established that local IgE production occurs within nasal polyp tissue, which may be amplified by bacterial superantigens, particularly from Staphylococcus aureus, which has been implicated in the pathogenesis of the disease. These superantigens can stimulate IgE production and exacerbate the inflammatory cycle within the sinonasal mucosa, worsening symptoms [106]. A recent randomized, double-blind, placebo-controlled trial involving patients with CRSwNP and coexisting asthma treated with omalizumab demonstrated a significant reduction in polyp size, along with improvements in bronchial and nasal symptoms, including smell, quality of life, and sinus CT scans. Patients with CRSwNP and co-morbid asthma, particularly following sinonasal surgery, may experience considerable clinical benefit from omalizumab therapy, affecting both the upper and lower airways [107]. Furthermore, omalizumab’s ability to inhibit IgE-mediated inflammation offers a promising approach in controlling the type 2 immune response in CRSwNP, where IgE-driven mechanisms play a pivotal role. As a result, omalizumab therapy may help to alleviate both the local and systemic aspects of the disease, thereby improving patient outcomes in the long term.

2.4.2. IL-4 and IL-13 Blockade

IL-4 and IL-13 are pivotal cytokines in type 2 (TH2) inflammation, driving eosinophilic infiltration, goblet cell hyperplasia, mucus overproduction, and epithelial barrier dysfunction. Their overlapping roles in promoting CRSwNP pathogenesis make them critical therapeutic targets. Both cytokines signal through the IL-4Rα, a shared receptor subunit. Dupilumab, a fully human monoclonal antibody, inhibits IL-4Rα, effectively blocking the signaling pathways of both IL-4 and IL-13. Clinical trials have demonstrated the profound impact of this dual-blockade strategy. In a study where patients received weekly dupilumab for 16 weeks, significant reductions in nasal polyp size, improvements in Lund–Mackay radiological scores, and enhanced olfactory function were observed. Moreover, dupilumab substantially improved patients’ quality of life, reducing symptoms like nasal congestion and restoring olfactory ability—outcomes that are particularly meaningful for those with severe, uncontrolled CRSwNP [108,109]. Beyond symptomatic relief, dupilumab’s ability to normalize inflammatory markers in both nasal and systemic compartments highlights its broader immunomodulatory effects. For instance, reductions in eosinophil-derived granule proteins, such as eosinophil cationic protein (ECP), and type 2 chemokines, including eotaxins, have been observed in treated patients. Dupilumab’s efficacy underscores the critical involvement of IL-4 and IL-13 in sustaining the inflammatory milieu of CRSwNP [109,110]. Emerging data also indicate its potential role in modifying disease progression. Recent studies suggest that early intervention with dupilumab may prevent epithelial remodeling and polyp recurrence by mitigating chronic inflammation. Future investigations into its long-term effects on epithelial barrier restoration and its utility in combination with other biologics could further refine its application in CRSwNP management [110]. In addition, the Phase II trial (CROWNS-1) showed that stapokibart (CM310), an IL-4Rα monoclonal antibody from China, effectively reduced daily symptoms and enhanced quality of life in patients with eosinophilic CRSwNP [111]. Tralokinumab and lebrikizumab are monoclonal antibodies designed to block IL-13. Although these therapies showed promise in preclinical models, clinical trials in patients with severe asthma did not achieve their main goals, despite the treatments being well tolerated and not linked to serious side effects. In contrast, dupilumab, which targets both IL-4 and IL-13 pathways, has shown significant benefits in reducing asthma exacerbations and improving lung function. This suggests that dual inhibition may be more effective than blocking IL-13 alone. Tralokinumab may still hold value for a narrow group of patients with high IL-13 activity [112].

2.4.3. Anti-IL-5 Blockade

IL-5 is a cornerstone cytokine in eosinophilic inflammation, central to eosinophil maturation, recruitment, and survival. Elevated IL-5 levels are a hallmark of eosinophilic CRSwNP, particularly in Caucasian populations, where it contributes to tissue damage and persistent inflammation. Targeting IL-5 or its receptor, IL-5Rα, represents a strategic approach to suppress eosinophilic activity and alleviate disease severity. Clinical trials of mepolizumab and reslizumab, two monoclonal antibodies that neutralize IL-5, have shown promising results. These agents effectively reduce blood and tissue eosinophil counts, decrease nasal polyp size, and alleviate CRSwNP symptoms, particularly in patients with elevated IL-5 levels in nasal secretions. Notably, mepolizumab has demonstrated sustained symptom relief and reduced the need for surgical interventions in patients with recurrent polyposis, as highlighted in randomized, placebo-controlled trials [58]. Fujieda et al. conducted a multicenter Phase III study across Japan, Russia, and China, which showed that mepolizumab was effective in eosinophilic CRSwNP [113].

Benralizumab, which targets IL-5Rα, provides an additional advantage by inducing antibody-dependent cell-mediated cytotoxicity (ADCC), leading to the direct depletion of eosinophils and basophils. This unique mechanism has shown potential in reducing airway eosinophilia and improving symptoms in eosinophilic asthma, and ongoing studies are exploring its utility in CRSwNP. While anti-IL-5 therapies primarily benefit eosinophilic CRSwNP, their broader implications for systemic eosinophilic disorders highlight their potential as multi-disease therapeutics. The development of biomarkers to predict IL-5-targeted therapy responsiveness remains an active area of research, aiming to optimize patient selection and therapeutic outcomes [114]. Across two identical international trials, a combined total of 528 patients were treated with either depemokimab—a twice-yearly, ultra-long-acting monoclonal antibody targeting IL-5—or a placebo. Treatment with depemokimab led to significant reductions in average nasal polyp size, nasal obstruction, and reliance on systemic corticosteroids. However, improvements in overall nasal symptom scores and the need for sinus surgery did not reach clinical significance [115].

2.4.4. IL-17 Blockade

IL-17, a cytokine family encompassing IL-17A, IL-17F, and IL-25, plays a dual role in immune defense and pathological inflammation. While IL-17A and IL-17F are more commonly associated with neutrophilic inflammation, IL-25 amplifies type 2 inflammation by acting on IL-17RA receptors. Brodalumab, a monoclonal antibody targeting IL-17RA, inhibits signaling from multiple IL-17 family members. Although studies in asthma patients treated with brodalumab did not demonstrate significant clinical efficacy, its role in CRSwNP remains underexplored. Preclinical data suggest that IL-17 blockade may hold promise for neutrophilic or mixed endotype CRSwNP, especially in patients unresponsive to type 2 biologics. Additional trials are necessary to clarify its role and refine its application, potentially in combination with therapies targeting other inflammatory pathways [116].

2.4.5. TSLP Blockade

Thymic stromal lymphopoietin (TSLP), an upstream alarmin released by damaged epithelial cells, plays a pivotal role in initiating type 2 inflammation by activating dendritic cells, group 2 innate lymphoid cells (ILC2s), and Th2 cells. By acting as a master regulator, TSLP amplifies the production of IL-4, IL-5, and IL-13, contributing to eosinophilic inflammation and barrier dysfunction in CRSwNP. Tezepelumab (Tezspire), an anti-TSLP monoclonal antibody approved by the FDA for asthma, has demonstrated substantial efficacy in asthma management. Clinical trials have shown that tezepelumab reduces asthma exacerbations by up to 71% per year, with parallel improvements in lung function and quality of life [117]. Given its role upstream of key type 2 cytokines, TSLP inhibition is a promising therapeutic avenue for eosinophilic CRSwNP. Emerging preclinical evidence suggests that tezepelumab may mitigate epithelial damage and reduce eosinophilic inflammation in murine models of nasal polyposis. Phase III trials in asthma are expected to yield critical insights into its broader applicability, including potential extensions to CRS management. Future studies in CRSwNP should explore its effects on epithelial integrity, biomarker modulation, and long-term outcomes in refractory cases [117]. In a multicenter clinical trial involving 203 patients with severe CRSwNP, participants were administered monthly subcutaneous injections of either tezepelumab or a placebo. After one year, those treated with tezepelumab showed significantly greater reductions in average nasal polyp size and symptom severity, along with a decreased need for systemic corticosteroids and additional sinus surgery [118]. However, CM326, a humanized monoclonal antibody targeting TSLP, showed superior potency to tezepelumab in reducing Th2-driven inflammation in preclinical studies. In clinical trials with healthy adults, CM326 was administered in single doses ranging from 22 to 880 mg and multiple doses up to 440 mg every two weeks (Q2W). It demonstrated linear pharmacokinetics, with accumulation ratios of AUC up to 4.04 and low rates of anti-drug antibody (ADA) formation. CM326 was well tolerated, showed low immunogenicity, and supports further investigation as a targeted therapy for Th2-mediated diseases [119].

Table 3. Targeted biologic therapies for CRSwNP.

Generic Name	Trade Name	Mechanism of Action	Indication/Current Status	Comments	Ref.
Omalizumab	Xolair	Anti-IgE via FcεRI receptor blockade	FDA-approved for CRSwNP	Reduces nasal polyp size and symptoms, particularly effective in patients with comorbid severe asthma	[106]
Mepolizumab	Nucala	Anti-IL-5 monoclonal antibody	FDA-approved for CRSwNP	Shown to reduce surgery needs and eosinophil levels in severe eosinophilic CRSwNP	[58]
Benralizumab	Fasenra	Anti-IL-5 via IL-5Rα receptor blockade	Phase III clinical trials	Efficacy in reducing eosinophilic inflammation and nasal polyps under investigation	[120]
Dupilumab	Dupixent	Anti-IL-4 and IL-13 via IL-4Rα receptor blockade	FDA-approved for CRSwNP	Demonstrated significant improvement in quality of life, olfactory function, and symptom control	[108]
Reslizumab	Cinqair	Anti-IL-5 monoclonal antibody	Phase II clinical trials	Reduces eosinophil counts; requires further study for full CRSwNP approval	[121]
Brodalumab	Siliq	Anti-IL-17 via IL-17RA receptor blockade	Preclinical/research stage	Limited efficacy in asthma; potential exploration in CRSwNP	[116]
Tezepelumab	Tezspire	TSLP blockade; upstream inhibition of IL-4, IL-5, IL-13	Phase III clinical trials	Promising results in asthma; potential for reducing type 2 inflammation in CRSwNP	[117]

Table 3. Targeted biologic therapies for CRSwNP.

Generic Name	Trade Name	Mechanism of Action	Indication/Current Status	Comments	Ref.
Omalizumab	Xolair	Anti-IgE via FcεRI receptor blockade	FDA-approved for CRSwNP	Reduces nasal polyp size and symptoms, particularly effective in patients with comorbid severe asthma	[106]
Mepolizumab	Nucala	Anti-IL-5 monoclonal antibody	FDA-approved for CRSwNP	Shown to reduce surgery needs and eosinophil levels in severe eosinophilic CRSwNP	[58]
Benralizumab	Fasenra	Anti-IL-5 via IL-5Rα receptor blockade	Phase III clinical trials	Efficacy in reducing eosinophilic inflammation and nasal polyps under investigation	[120]
Dupilumab	Dupixent	Anti-IL-4 and IL-13 via IL-4Rα receptor blockade	FDA-approved for CRSwNP	Demonstrated significant improvement in quality of life, olfactory function, and symptom control	[108]
Reslizumab	Cinqair	Anti-IL-5 monoclonal antibody	Phase II clinical trials	Reduces eosinophil counts; requires further study for full CRSwNP approval	[121]
Brodalumab	Siliq	Anti-IL-17 via IL-17RA receptor blockade	Preclinical/research stage	Limited efficacy in asthma; potential exploration in CRSwNP	[116]
Tezepelumab	Tezspire	TSLP blockade; upstream inhibition of IL-4, IL-5, IL-13	Phase III clinical trials	Promising results in asthma; potential for reducing type 2 inflammation in CRSwNP	[117]

3. Conclusions

Chronic rhinosinusitis (CRS), particularly CRSwNP, represents a complex and heterogeneous inflammatory condition driven by diverse immunopathogenic mechanisms. Cytokines such as IL-4, IL-5, IL-13, and IL-17 play pivotal roles in mediating type 2 immune responses, leading to eosinophilic inflammation, epithelial barrier dysfunction, and the formation of nasal polyps. The intricate interplay between these cytokines and their receptors highlights the multifaceted nature of CRS pathogenesis and underscores the potential for targeted therapeutic interventions. Personalized medicine has emerged as a transformative approach to CRS management, emphasizing tailored treatments based on individual characteristics, including disease phenotype, immune profile, and therapeutic responsiveness. The identification of reliable biomarkers through advanced techniques such as cytokine detection, cellular profiling, and transcriptomics is instrumental in refining CRS endotypes and enabling precise disease monitoring. Biologic therapies targeting key cytokines, such as IL-4, IL-5, and IgE, have shown remarkable efficacy in improving clinical outcomes, particularly for CRSwNP patients with severe or refractory disease, including those with comorbid asthma. These advancements signify a paradigm shift in CRS management, offering the promise of improved quality of life and disease control through precision-based, individualized care.