T2-Low Asthma: Mechanistic Pathways, Biomarkers, and Emerging Therapeutic Strategies

OBJECTIVE: To synthesize current definitions, mechanistic pathways, biomarker limitations, and evidence-graded therapeutic strategies for T2-low asthma as a heterogeneous clinical and translational construct. DATA SOURCES: This narrative review searched PubMed/MEDLINE, Embase, the Cochrane Library, and reference lists of key articles from database inception to June 2026. STUDY SELECTIONS: Peer-reviewed human studies, randomized trials, post hoc analyses, systematic reviews, meta-analyses, guidelines, severe-asthma registries, biomarker cohorts, and mechanistic asthma studies were prioritized. Preclinical studies were used only when human evidence was limited and were interpreted as hypothesis-generating. RESULTS: T2-low asthma is usually defined by low eosinophils, low fractional exhaled nitric oxide, and limited evidence of canonical type 2 inflammation, but this remains an exclusionary definition. The construct includes neutrophilic, paucigranulocytic, obesity-associated, exposure-related, infection-linked, bronchiectasis-overlap, and remodeling-dominant presentations. Candidate pathways include Th1/Th17 signaling, CXCL8/CXCR2-mediated neutrophil recruitment, inflammasome activation, IL-6-associated immunometabolic inflammation, epithelial alarmins, dysbiosis, and small-airway dysfunction. No positive biomarker currently identifies treatment-responsive T2-low asthma in routine practice. Management relies on diagnostic confirmation, optimized inhaled therapy, repeated phenotyping, treatable-traits care, and selected add-on options including tezepelumab, azithromycin, or bronchial thermoplasty in appropriate patients. A total of 63 references were synthesized in this review. CONCLUSION: T2-low asthma is clinically important but mechanistically diverse. Progress requires validated positive biomarkers, harmonized phenotyping, and biomarker-enriched trials that test therapies in coherent subgroups without overstating readiness for routine care.