Chronic rhinosinusitis (CRS) is defined by persistent sinonasal symptoms with objective evidence of mucosal inflammation for at least 12 weeks. Clinical classification still begins with CRS without nasal polyps (CRSsNP) and CRS with nasal polyps (CRSwNP), but phenotype does not map cleanly onto inflammatory biology. Patients with the same phenotype may show different immune signatures, while similar endotypes can occur across polyp and non-polyp disease. This has shifted the field toward classification by dominant immunopathologic pathways [1-2].

      For this review, non-type 2 disease refers to type 1 and/or type 3 inflammation. Type 1 disease is associated with interferon-gamma and a neutrophil-predominant profile; type 3 disease is associated with interleukin (IL)-17 and IL-22 and is also commonly neutrophilic. Mixed disease refers principally to concurrent type 2 and type 3 signals. These categories overlap and are not yet defined by a single transferable clinical standard [1]. Type 2 inflammation predominates in many Western CRSwNP cohorts, whereas non-type 2 and mixed signatures represent a larger share of severe CRSsNP and of CRSwNP in several East Asian cohorts [3].

    This distinction has direct therapeutic consequences. Dupilumab, omalizumab, mepolizumab, and tezepelumab were validated in severe CRSwNP populations whose clinical and biological features substantially overlap with type 2 inflammation [4-7]. Their efficacy has not been established in cohorts prospectively defined by dominant type 1 or type 3 inflammation. The central problem is therefore not whether patients with non-type 2 disease have treatment options at all, because conventional medical therapy and endoscopic sinus surgery remain important across endotypes, but whether they have validated endotype-directed pharmacologic therapy and a practical way to be selected for it [1,8].

        Previous reviews have described non-type 2 and mixed inflammation, the expanding biologic landscape, and contemporary CRS management [[9-11]. The European Academy of Allergy  and   Clinical   Immunology Task Force has separately emphasized the difficulty of translating endotype definitions into routine care [12]. This review takes a narrower therapeutic perspective: which patients remain outside the validated reach of current biologics, what evidence supports proposed alternatives, and what prevents those alternatives from being tested rationally? PubMed/MEDLINE, Embase, the Cochrane Library, ClinicalTrials.gov, and regulatory sources were reviewed from database inception through 27 July 2026. Evidence was prioritized from guidelines and phase 3 randomized trials to earlier clinical and preclinical studies. Direct evidence in prospectively defined non-type 2 disease was considered separately from evidence obtained in unselected CRSwNP.

Endotype Biology and The Biomarker Bottleneck

Type 2 CRS is comparatively mature as a therapeutic endotype because its biology can be approximated clinically. Eosinophilic inflammation, local or systemic immunoglobulin E, asthma, aspirin-exacerbated respiratory disease, and tissue eosinophilia are recognizable features, while blood eosinophils and total or specific immunoglobulin E are routinely accessible surrogates. Type 1 and type 3 disease remain defined largely by tissue cellularity, cytokine assays, or research transcriptional signatures [2,12-13].

The sinonasal epithelium is both a barrier and an immunologic sensor. Epithelial injury can initiate downstream inflammation through alarmins such as thymic stromal lymphopoietin, IL-25, and IL-33. This creates a mechanistic rationale for upstream blockade, but it does not establish efficacy in a prospectively defined non-type 2 population [13-14]. Microbial factors further complicate endotyping: Staphylococcus aureus superantigens can amplify local immunoglobulin E and type 2 inflammation, while biofilm-associated dysbiosis can sustain broader epithelial and innate activation [15-16].

Neutrophilia is not synonymous with a type 3 endotype. Neutrophils may accompany type 1 or type 3 programmes, infection, barrier injury, corticosteroid exposure, or mixed inflammation. In Japanese CRSwNP tissue, non-eosinophilic samples have demonstrated stronger type 1/type 3 signals, illustrating both biologic and geographic heterogeneity [17]. Chronic inflammation also produces structural remodelling that may persist after short-term inflammatory control, so improvement in polyp score should not automatically be interpreted as disease modification [18].

The practical bottleneck is therefore biomarker translation. Periostin and tissue eosinophilia correlate with eosinophilic disease in selected cohorts, but periostin is not routinely available and even type 2 markers do not reliably rank one biologic above another for an individual patient [19]. For type 1, type 3, and mixed disease, there is no validated point-of-care assay that prospectively identifies the relevant inflammatory programme. Tissue neutrophilia, interferon-gamma, IL-17A, and IL-22 remain predominantly research measurements. A marker that predicts recurrence is also not necessarily a predictive biomarker for treatment response; the clinically useful standard is a treatment-by-biomarker interaction, not merely correlation with severe disease.The endotype-treatment gap is illustrated in Figure 1.

Figure 1: Classification of Chronic Rhinosinusitis (CRS) Based on Inflammatory Endotypes

Table 1 summarizes the principal endotypes and barriers to clinical translation.

Table 1: Chronic Rhinosinusitis Endotypes and Clinical Translation

AERD, aspirin-exacerbated respiratory disease; IFN, interferon; IL, interleukin; ILC, innate lymphoid cell; NK, natural killer. Non-type 2 denotes type 1 and/or type 3 predominance. Routine availability varies by center; cytokine-level endotyping remains predominantly research-based

Type 2 Biologics and The Boundary of Current Evidence

The strongest therapeutic evidence in CRS remains concentrated in severe CRSwNP. Dupilumab improved nasal polyp score, congestion, and computed tomography opacification in SINUS-24/52; omalizumab improved polyp and congestion outcomes in POLYP 1/2; and mepolizumab improved polyp burden and nasal obstruction in SYNAPSE [4-6]. These trials establish efficacy in the clinical phenotype studied, but not in patients prospectively selected for dominant type 1 or type 3 inflammation.

Tezepelumab blocks thymic stromal lymphopoietin upstream of several downstream inflammatory pathways. WAYPOINT demonstrated improvements in nasal polyp score and a substantial reduction in the need for surgery or systemic corticosteroids [7]. Its upstream position is mechanistically broader than downstream IL-4-, immunoglobulin E-, or IL-5-directed agents, yet endotype-specific efficacy outside type 2-predominant disease remains unproven. A pooled safety analysis has prompted attention to infectious events, supporting surveillance rather than a presumed causal class effect [20].

The biologic landscape continues to expand. Stapokibart extends IL-4 receptor alpha blockade and has phase 3 efficacy data [21-22]. Benralizumab improved polyp and blockage scores in OSTRO and produced an exploratory reduction in tissue IL-17A; that biomarker change does not establish efficacy in mixed or type 3 disease [23]. Depemokimab improved polyp and obstruction scores in ANCHOR-1/2 with twice-yearly dosing [24]. Other programmes target thymic stromal lymphopoietin, IL-4 receptor alpha, IL-13, or combined epithelial/type 2 pathways, including TQC2731, GR1802, CM512, lebrikizumab, and lunsekimig [25-29]. The pipeline may broaden choice and dosing convenience, but most candidates still address type 2 or epithelial-alarmin biology rather than a validated non-type 2 pathway.

Negative studies are equally informative. The oral CRTH2 antagonist AZD1981 did not significantly reduce nasal polyp score despite a plausible type 2 rationale, and ruxolitinib remains preclinical in CRS despite encouraging epithelial and inflammatory effects in a murine model [30-31]. These examples caution against equating pathway plausibility with clinical benefit. Table 2 summarizes approved and late-stage biologic therapies.

Table 2: Approved and Late-Stage Biologic Therapies in Crswnp

CRSwNP, chronic rhinosinusitis with nasal polyps; TSLP, thymic stromal lymphopoietin. Regulatory status is reported as of 27 July 2026. “Not established” means that efficacy has not been demonstrated in a cohort prospectively defined by a non-type 2 biomarker or endotype criterion

The Non-Type 2 Therapeutic Gap

No biologic is approved specifically for prospectively defined type 1 or type 3 CRS. This does not exclude benefit in mixed disease, but efficacy from type 2-predominant CRSwNP trials  cannot   be  transferred    automatically   to patients whose dominant inflammation is neutrophilic or IL-17-associated. The absence of a targeted option partly reflects trial design: phenotype, severity, prior surgery, and corticosteroid exposure are easy to define at scale, whereas cytokine endotyping requires tissue or specialized assays.

IL-17 blockade is the most visible candidate for type 3 disease, but the clinical evidence remains extremely early. A 2024 report described two patients with mixed type 2/type 3 CRSwNP who improved in nasal polyp score and     the     22-item    Sino-Nasal   Outcome    Test    after  incomplete response to dupilumab [32]. This observation is hypothesis-generating. It cannot distinguish drug effect from regression to the mean, concurrent therapy, or imperfect baseline endotyping, and no controlled CRS trial has established efficacy for secukinumab or brodalumab.

The key limitation is therefore diagnostic as much as pharmacologic. Broad “non-type 2” labels may combine biologically distinct type 1, type 3, infection-associated, and mixed inflammatory states. Without a clinically deployable way to identify those states before treatment, a trial may dilute a true subgroup effect and clinicians cannot rationally select an off-label targeted therapy.

Emerging Strategies Outside Conventional Cytokine Blockade

Several investigational approaches act on the epithelial barrier, local microbiome, or sinonasal physiology rather than a defined cytokine axis. Mesenchymal stem-cell strategies have produced histologic improvement in an animal CRS model, while human evidence remains limited to an abstract-level report and does not establish clinical efficacy [33-34].

Bacteriophage therapy has reached human safety testing. In a first-in-human phase 1 study, intranasal AB-SA01 was given to nine patients with recalcitrant Staphylococcus aureus CRS; treatment was well tolerated and two patients achieved microbiologic eradication [35]. This establishes feasibility and short-term safety, not therapeutic efficacy. Microbiome-directed treatment is less encouraging: a 2025 systematic review and meta-analysis of probiotics found no consistent clinically meaningful improvement in the 22-item Sino-Nasal Outcome Test [36].

Topical antimicrobial strategies have likewise failed to show convincing disease-modifying benefit. Manuka honey did not outperform saline in general recalcitrant CRS, and colloidal silver showed no meaningful advantage over saline in randomized testing [37-38]. Acoustic and vibrational approaches remain hypothesis-generating. A recent review described physiologic rationale and limited CRS data, whereas the strongest sham-controlled evidence for acoustic resonance therapy is in rhinitis rather than CRS [39-40]. Table 3 summarizes investigational strategies and the maturity of their evidence.

Figure 1 Endotype-treatment gap in chronic rhinosinusitis. The schematic contrasts the comparatively mature type 2 pathway, for which routinely available biomarkers and multiple approved biologics exist, with type 1 and type 3 disease, for which clinically deployable biomarkers and approved endotype-directed therapies are lacking. Routine type 2 markers include blood eosinophils and total or specific immunoglobulin E; tissue eosinophilia is available when histology has been obtained, whereas periostin and cytokine-level assays remain non-routine. Mixed type 2/type 3 inflammation may contribute to incomplete response to type 2-directed treatment but remains difficult to define prospectively. CRS, chronic rhinosinusitis; CRSsNP, chronic rhinosinusitis without nasal polyps; CRSwNP, chronic rhinosinusitis with nasal polyps; AERD, aspirin-exacerbated respiratory disease.

Table 3: Investigational Non-Type 2, Microbial, Regenerative, and Non-Pharmacologic Strategies in CRS

CRS, chronic rhinosinusitis; NPS, nasal polyp score; SNOT-22, 22-item Sino-Nasal Outcome Test. Evidence is classified by the most direct CRS-specific human evidence available through 27 July 2026

The therapeutic asymmetry across CRS endotypes is now clear. Type 2 disease has multiple validated drug targets and clinically accessible surrogate markers, whereas type 1, type 3, and mixed inflammation have neither a routine diagnostic assay nor an approved endotype-directed treatment pathway. The result is a field in which therapeutic sophistication has outpaced diagnostic precision.

This has several implications for clinical practice. First, treatment failure should not be used as retrospective proof of a non-type 2 endotype. Failure may reflect disease severity, adherence, inadequate exposure, structural disease, comorbidity, or mixed inflammation. Second, routine type 2 markers can support endotype-level triage but do not constitute a validated algorithm for ranking biologics. Third, suspected non-type 2 or mixed disease should not by itself become an indication for off-label cytokine blockade; where available, clinical-trial enrolment and research-grade tissue or mucus endotyping are preferable.

Future trials should prespecify endotype definitions, assay methods and thresholds, geography, prior corticosteroid and biologic exposure, and both patient-reported and objective outcomes. IL-17 and other neutrophil-directed programmes are especially vulnerable to signal dilution if mixed and type 2-predominant disease are enrolled without stratification. Long-term studies should also distinguish short-term inflammatory control from modification of remodelling, recurrence, surgery, and treatment dependence.

This review is intentionally narrative rather than systematic. Source selection was based on relevance to prespecified domains, no formal risk-of-bias instrument was applied, and no pooled treatment estimates were calculated. The evidence spans phase 3 biologic trials, case-level observations, antimicrobial safety studies, device trials, and preclinical regenerative work. The synthesis should therefore be read as a critical map of therapeutic maturity and evidence directness rather than a comparative effectiveness analysis.

Biologic therapy has transformed severe type 2-predominant CRSwNP, but equivalent progress has not occurred for patients with dominant type 1, type 3, or mixed inflammation. The emerging alternatives remain early: IL-17 blockade is supported only by case-level observations, bacteriophage therapy has established feasibility rather than efficacy, regenerative strategies remain largely preclinical, and microbiome-directed or physical interventions have limited or negative controlled evidence.

The most important barrier may therefore be diagnostic. Progress beyond type 2 CRS will require clinically deployable biomarkers that identify inflammatory state before treatment, standardized prospective definitions, and endotype-enriched trials capable of testing whether a mechanistically plausible therapy benefits the patients it was designed to reach.

Acknowledgment

None.

Conflict of Interest

The authors declare that they have no conflict of interest.

Funding

No funding was received for the preparation of this manuscript.

Ethical Approval

Not applicable. This narrative review did not involve human participants, animals, or newly collected biological material.

Informed consent

Not applicable. This narrative review contains no individual participant data or identifiable patient information.

Author contributions

Both authors contributed to the conception of the review, literature evaluation, interpretation of the evidence, drafting of the manuscript, and critical revision for important intellectual content. Both authors are accountable for the integrity of the work.

Data Availability

No new datasets were generated or analysed for this narrative review.

Artificial Intelligence Disclosure

ChatGPT (OpenAI) was used to assist with language editing, manuscript organization, and journal formatting. The authors are responsible for verifying the scientific content and references and for approving the final manuscript.

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