Asthma at the crossroads: From anti-TNF-α setbacks to next-generation biologics targeting type 1 and type 2 inflammation.

Severe asthma remains a major unmet clinical challenge due to its marked immunological heterogeneity and the limited efficacy of current therapies in non-Type 2 inflammatory endotypes. Although biologics targeting IL-4, IL-5, and IL-13 have significantly improved outcomes in eosinophilic asthma, therapeutic options for Type 1 and mixed inflammatory phenotypes remain inadequate. The failure of anti-TNF-α therapies highlighted critical translational barriers including cytokine redundancy, insufficient endotype stratification, and systemic safety concerns, thereby reshaping the direction of respiratory immunopharmacology toward precision-guided intervention strategies. This review critically examines the immunobiology of Type 1 and Type 2 inflammation, evaluates the mechanistic and clinical lessons derived from anti-TNF-α trials, and discusses emerging therapeutic platforms including nanobodies, RNA-based therapeutics, gene-editing technologies, cell-based immunotherapies, and advanced pulmonary delivery systems. Furthermore, the review highlights the growing role of multi-omics biomarkers, microbiome profiling, and artificial intelligence in enabling adaptive and personalized asthma management. Collectively, these advances support a transition from generalized cytokine blockade toward integrated immune-network modulation for severe asthma across diverse inflammatory endotypes.